An effective process for conversion of diphenylurea to CC-2, a potential decontaminant of sulfur mustard

Article abstract of DOI:10.1021/op060002p

N,N′-Dichlorobis(2,4,6-trichlorodiphenyl) urea, also known as 2-chlorocarbinol (CC-2) is a potential decontaminant of Sulfur Mustard (SM), which is also known as bis(2-chloroethyl) sulfide (HD), a well-known warfare agent. A new process has been developed

Full text of DOI:10.1021/op060002p

Organic Process Research & Development 2006, 10, 505−511
An Effective Process for Conversion of Diphenylurea to CC-2, a Potential
Decontaminant of Sulfur Mustard
Bidhan C. Bag,*,† Krishnamurthy Sekhar,† Devendra K. Dubey,† Makireddi Sai,† Rajendra S. Dangi,†
Mahavir P. Kaushik,† and Chiranjib Bhattacharya‡
Process Technology DeVelopment DiVision, Defence Research & DeVelopment Establishment, Ministry of Defence,
GoVernment of India, Jhansi Road, Gwalior - 474 002, India, and Department of Chemical Engineering, JadaVpur
UniVersity, Kolkata - 700 032, India
Abstract:
Decontamination of chemical warfare agents (CWAs) is
required in the case of chemical attack by adversaries or
terrorists. Decontamination is one of the important combating
activities (detection, protection, and decontamination) against
CWAs. Decontamination of CWAs is achieved either by
physically removing the toxic substances from contaminated
surfaces (materials in the field like vehicles, buildings,
equipment, and living objects) or by chemically converting
them into relatively less or nontoxic substances.10 For
physical removal of CWAs from a contaminated site,
adsorbents such as Fuller’s earth (native aluminium silicate)
and detergent/soap solutions are used. Since these decon-
taminants do not detoxify the toxic agents, they are not
considered as reliable means. The second major problem of
physical decontaminants is their safe disposal. Physical
decontaminants themselves get contaminated during decon-
tamination operation; their subsequent safe disposal requires
further treatment to neutralise CWAs. Another problem of
physical decontaminants is secondary contamination, which
is caused by the ensuing desorption of adsorbed CWAs. Yet
another problem of physical decontaminants such as washing
solutions is spreading of the contaminated area, since during
washing operation the solution is spread over the contami-
nated surface.
Keeping in view the hazards of SM, its decontamination
is of paramount importance. It is required on the battlefield,
laboratories, production and storage plants, destruction sites,
and more importantly in case of sabotage and usage of CWAs
by terrorists. In all cases the chemical decontamination of
the HD is still the best method of protection against HD.11
Currently used reactive decontaminants include nucleophile/
base-amine mixtures and bleach formulations.12-14 Although
these formulations are effective in decontaminating the
CWAs, they cannot be used on persons because they are
highly corrosive and toxic and hence best suited for material
decontamination only. Consequently, there was a need to
develop a safe and effective decontamination formulation
against CWAs for human application.
N,N′-Dichlorobis(2,4,6-trichlorodiphenyl) urea, also known as
2-chlorocarbinol (CC-2) is a potential decontaminant of Sulfur
Mustard (SM), which is also known as bis(2-chloroethyl) sulfide
(HD), a well-known warfare agent. A new process has been
developed for the synthesis of CC-2 from diphenylurea (DPU)
through an intermediate, known as hexachlorocarbanilide
(HCC). The conversion of DPU to HCC was studied in the
temperature range 35-100 °C in the presence of several
homogeneous scavengers of HCl, like pyridine, triethylamine,
ethylenediamine, hexamethylenetetramine, 4,4′-bipyridine, di-
ethylamine, dicyclohexylamine, etc. Experiments were carried
out to study the activity of these homogeneous scavengers to
get maximum conversion, yield, and purity of the product.
Reaction temperature, reaction time, substrate-to-scavenger
ratio, and solvent requirements were studied to optimize the
reaction conditions. Both pyridine (product purity ∼80% and
yield ∼89%) and ethylenediamine (product purity ∼85% and
yield ∼70%) were found to be effective in improving the
performance of the reaction.
Introduction
Sulfur Mustard (SM), also known as bis(2-chloroethyl)
sulfide (HD) is a chemical warfare agent with serious toxic
effects. SM causes serious blisters upon contact with human
skin, and due to this reason it has been used as a chemical
warfare agent.1-9 There also exists the potential threat of
use of SM by a terrorist group. So, protection of the soldiers
and the civilians against HD remains one of the main
concerns of the scientific community. However, there is no
specific antidote available against HD.
* Corresponding author. E-mail: b_bag@rediffmail.com. Fax: 00-91-751-
2341148.
† Ministry of Defence, Government of India.
‡ Jadavpur University.
(1) Rao, P. V. L.; Vijayaraghavan, R.; Bhaskar, A. S. B. Toxicology 1999, 139,
39.
(2) Somani, S. M.; Babu, S. R. Int. J. Clin. Pharmacol., Ther. Toxicol. 1989,
27, 419.
(3) Dacre, J. C.; Goldman, M. Pharmacol. ReV. 1996, 290.
(4) Pechura, C. M.; Rall, D. P. Veterans at Risk: The Health effects of Mustard
Gas and Lewisit; National Academy Press: Washington, DC, 1993.
(5) Wormser, U. Trends Pharmacol. Sci. 1991, 12, 164.
(6) Smith, W. J.; Dunn, M. A. Arch. Dermatol. 1991, 127, 1207.
(7) Eisenmenger, W.; Drasch, G.; Clarmann, M. V.; Kretschmer, E.; Roider,
G. J. Forensic Sci. 1991, 36, 1688.
A requirement for a topical skin protectant (TSP) to
protect skin from toxic CWAs was immediately recognised
(10) Trapp, R. The Detoxification and Natural Degradation of Chemical Warfare
Agents; Stockholm International Peace Research Institute, SIPRI, Taylor
& Francis: London and Philadelphia, 1985.
(8) Momeni, A. Z.; Enshaeih, S.; Meghdadi, M.; Amindjavaheri, M. Arch.
Dermatol. 1992, 128, 775.
(9) Papirmeister, B.; Feister, A. J.; Robinson, S. I.; Ford, R. D. Medical Defence
Against Mustard Gas; CRC Press: Boca Raton, FL, 1991.
(11) Yang, Y.C. Chem. Ind. 1995, 1, 334.
(12) Yang, Y. C.; Baker, J. A.; Ward, J. R. Chem. ReV. 1992, 92, 1729.
(13) Seiders, R. P. U.S. Patent H366, 1987.
(14) Norman, G. Int. Patent A62D3/00 & Eur. Patent A62D3/00E, 1998.
10.1021/op060002p CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/30/2006
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following the introduction of these agents in World War I.
Although several creams and ointments were made, none of
them was effective in deactivating the CWAs. Just prior to
and during World War II, a concentrated effort to develop
ointments for protection against sulphur mustard was made
at the chemical warfare service in Edgewood Arsenal,
Maryland USA, which resulted in the development of M-5
ointment, but it left room for improvement. For several years,
research concentrated on introducing active ingredients such
as alkalies, chelators, sorbents, etc. into polyethylene-based
formulations. However, none of them provided the required
protection.15
Recently, two compounds have been used as active
ingredients in the formulations made to protect human skin
from sulphur mustard. A substance coded as S-330 (1,3,4,6-
tetrachloro-7,8-diphenyl-2,5-diiminoglycoluril) was mixed
with perfluorinated ethers and evaluated as a reactive
decontaminant against sulphur mustard.16,17 But the main
disadvantages of this system are the use of an uneconomic
and nonecofriendly perfluorinated compound as base mate-
rial, and S-330 decomposes within 2-3 weeks at room
temperature in the presence of even a little moisture. Another
disadvantage of this system is that it is not very fast acting,
which is the prime requirement of any decontaminant.18,19
The second compound which was found to be very efficient,
fast acting, and effective at subzero temperatures also in
decontaminating the sulphur mustard is N,N′-dichlorobis-
(2,4,6-trichlorophenyl) urea (1).20 It is a solid at room-
competent authority for introduction into services after
passing through necessary toxicological and pharmacological
tests and trials.21,22 Keeping in view the requirement of
formulation based on 1 in large quantities, there is a need to
develop the technology for preparation of 1 itself. The
methods reported in the literature for preparation of 1 are
inadequate in meeting the requirement of an industrially
viable process. In one method, 1 is prepared by reacting
diphenylurea (10) with chlorine for 48 h in two steps.23 The
major disadvantages of the process are that complete
chlorination of aromatic rings did not take place in this
method, the yield of the product is less (<40%), the rate of
reaction is very slow, and it takes 7 days (with 40% yield)
for aromatic chlorination and 48 h for N-chlorination (second
step) (with ≈ 30-40%), and also several impurities are
formed (partial chlorinated products). The second method
makes use of phosgene, which is reacted with 2,4,6-
trichloroaniline to produce HCC-2 (11), the precursor of 1.
In a second step, 11 is converted into 1 by reacting it with
chlorine.24 Both methods are not suitable for production of
1 in large amounts, as they are time-consuming and multistep
and involve highly toxic phosgene as a starting material.
Keeping in view limitations of existing synthetic proce-
dures of 1, there was a dire need to develop an industrially
viable process for the production of 1. More importantly,
there was a need for development of a one-pot process
(without any requirement of isolation of intermediates or
precursors) to produce 1 by making use of readily available
chemicals.
A new laboratory method for the synthesis of 1 has been
reported.20 According to the process, 1 can be synthesized
from 10 through a two-stage chlorination process. But the
process has some bottlenecks. First, the product contains a
lot of impurities such as 2, 3, 4, 5, 6, 7, 8, and 9 that are
produced through an incomplete reaction. Once these impuri-
temperature having a melting point of 178-180 °C. Theo-
retically 1 contains 14.54% active chlorine, which is
responsible for the instantaneous reaction with HD. Therefore
1 can be used for personal protection against SM on the
battlefield. Formulations made by incorporating 1 in different
bases such as Gum acacia and hydroxypropyl cellulose were
found to be very effective, stable, and safe and provided the
best protection against topically applied sulphur mustard in
mice and rats. Since SM is highly lipophilic and gets
absorbed very quickly after contact with skin, the best way
of protection from SM is to decontaminate it instantaneously
after contact with skin without causing any damage to
delicate human skin. This stringent requirement of decon-
taminant was successfully met by developing a formulation
based on 1 that deactivated the topically applied SM
instantaneously without causing any irritation or harm to the
skin. A formulation based on 1 has been approved by
(15) Liu, D. K.; Wannemacher, R. W.; Snider, T. H.; Hayes, T. L. J. Appl.
Toxicol. 1999, 19, 541.
(16) Speck, J. C., Jr. U.S. Patent No. 5607, 1997.
(17) Shih, M. L.; Korte, W. D.; Smith, J. R.; Szfraniec, L. L. J. Appl. Toxicol.
1999, 19, S89.
(18) Brau, E. H. J. Appl. Toxicol. 1999, 19, S47.
(19) Koper, O.; Lucas, E.; Klabunde, K. J. J. Appl. Toxicol. 1999, 19, S59.
(20) Dubey, D. K.; Malhotra, R. C.; Vaidyanathaswamy, R.; Vijayaraghava, R.
J. Org. Chem. 1999, 64, 8031.
ties are formed it is very difficult (almost impossible) to
separate them by any separation process, in an economical
manner. Second, even if all the impurities are separated, then
506
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Vol. 10, No. 3, 2006 / Organic Process Research & Development

Scheme 1. Conversion of 10 to 1 through aromatic and
N-chlorination
Scheme 2. Mechanism of formation of mono- and
disubstituted impurities of 11
the overall yield of the pure product is very less. Hence,
new reactions were tried in the presence of a scavenger to
enhance the conversion towards the desired product and
thereby increase the yield of product by restricting conver-
sions towards impurities. In this paper all the activities of
different scavengers to remove the impurities were explained.
The effect of each scavenger on the yield and the conversion
has also been described in this paper.
Results and Discussion
The conversion of 10 to 1 takes place in two steps, where
in the first step aromatic chlorination takes place and the
second step is the N-chlorination. Chlorine is absorbed by
the reaction mixture, where chlorination of phenyl rings takes
place at 2,4,6 positions as shown in Scheme 1 first and then
N-chlorination takes place in an acetic acid and sodium
hydroxide mixture at a pH of 7.0. As the reaction proceeds
and aromatic chlorination was achieved, the precipitation of
11 occurs and absorption of chlorine gas gradually ceases.
This initial aromatic chlorination is complete within 4-6 h,
which was indicated by the appearance of a fluffy precipitate
of 11 and the IR and NMR analyses. In this reaction one of
the major disadvantages is that a lot of impurities as described
in the previous section were formed, and the formation of
these impurities is explained as incomplete chlorination of
the aromatic ring (Scheme 2). The mechanism of conversion
of 11 to 1 is explained in the Scheme 3. The N-chlorination
takes place via the formation of hypochlorous acid, in which
chlorine has a slight positive charge. This positive charge
on chlorine is responsible for the attack of the lone pair on
the nitrogen of 11.
Scheme 3. Mechanism of N-chlorination of 11
possible to separate them by any economical separation
technique. Therefore, the second step (N-chlorination) was
continued in the same reactor, and all the partial aromatic
chlorinated intermediates had undergone N-chlorination in
the second step (in the same reactor) and became impurities
with the desired 1. Since, in the second step, all the
intermediates, whether partially or completely chlorinated
in the phenyl group, undergo N-chlorination and contribute
to the lower conversion towards the desired product, the
purity (<50%) and the yield (only 80%) are also less. In
this case the product was yellowish due to the presence of
impurities. Also, it is not possible to separate these impurities
from 1 by any separation process economically. Even several
recrystallizations of 1 could not lead to a product of more
than 90% pure. It was observed that in the presence of
impurities the product becomes unstable and the colour
changes to reddish yellow with time.
Reaction without a Scavenger. By performing the
reaction without a scavenger it was observed that incomplete
aromatic ring chlorination products (mono- and bisubstituted)
are formed as impurities. These impurities are formed
through a series reaction due to the incomplete chlorination
of the aromatic ring. It was observed that once partial
chlorinated products were formed as impurities, it was not
(21) Vijayraghavan, R.; Kumar, P.; Dubey, D. K.; Singh, R. Biomedical and
EnVironmental Sciences 2002, 15, 25.
(22) Vijayraghavan, R.; Kumar, P.; Dubey, D. K.; Singh, R.; Sachan, A. S.;
Pant, S. C.; Bhattacharya, R. Ind. J. Pharmacol. 2002, 34, 321.
(23) Chattaway, F. D.; Orton, K. J. P. Berichte 1901, 34, 1073.
(24) Pfansteil, R.; Pralatowski, F. M.; Scruton, H. A. U.S. Patent 2936322, 1960.
Effect of Reaction Temperature. For studying the effect
of temperature on the yield, conversion, and purity of
Vol. 10, No. 3, 2006 / Organic Process Research & Development
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Table 1. Results of reaction carried out in the presence of different scavengersa
scavenger
no.
moles of
scavenger
molar ratio
(scavenger/DPU)
yield
(%)
% purity
of 1
scavenger
pyridine
1
0.0030
0.0120
0.0310
0.0620
0.0920
0.1220
0.1470
0.1840
0.2810
0.0070
0.0374
0.0750
0.1220
0.1500
0.1800
0.00043
0.0009
0.0018
0.0036
0.0047
0.0357
0.0710
0.0064
0.0160
0.0320
0.0025
0.0050
0.0125
0.0250
0.0500
0.1004
0.0247
0.0494
0.0988
0.148
0.0667
0.2667
0.6889
1.3778
2.0444
2.7111
3.2667
4.0888
6.2444
0.1555
0.8311
1.6667
2.7111
3.3333
4.0000
0.0096
0.0200
0.0400
0.0800
0.1044
0.7933
1.5778
0.1422
0.3556
0.7111
0.0556
0.1111
0.2778
0.5556
1.1111
2.2311
0.5488
1.0978
2.1956
3.2889
54.2
55.0
59.4
68.2
74.3
82.0
79.0
78.2
68.9
64.0
65.0
77.0
64.2
45.7
41.0
32.0
59.5
54.8
48.0
43.0
27.4
00.0
32.0
54.9
57.1
36.0
36.6
27.4
27.4
25.2
12.0
45.7
44.0
54.8
68.6
62.8
65.6
69.2
75.6
78.2
80.3
77.3
74.3
58.3
62.0
75.0
85.0
84.2
80.2
55.0
31.0
35.0
33.0
34.0
32.2
00.0
00.0
88.4
75.6
33.4
2
3
ethylenediamine
hexamethylenetetramine
4
5
bypyridine
dicyclohexylamine
6
triethylamine
29.6
34.8
43.2
53.2
a Conditions: substrate (DPU), 0.045 mol; reaction temperature in first step, 80-82 °C; reaction temperature in second step, 10-15 °C; reaction time, 8 h (4 h in
first step and 4 h in second step).
product, experiments were carried out at different temper-
atures. The aromatic chlorination and the N-chlorination were
carried out in the temperature range 30 to 80 °C and 5 to 40
°C, respectively. The reactions were allowed to complete
by bubbling chlorine for 4 h in both reaction steps. To see
the effect of temperature on each step separately, the product
mixture was filtered and 11, formed in the reaction, was
separated. With an increase in the temperature the solubility
of chlorine decreases, but the rate of reaction increases. The
experimental results suggest that the optimum temperature
in aromatic chlorination (first step reaction) is 80-82 °C. It
was observed that below this temperature the yield of HCC
was less due to less reactivity at lower temperature, whereas
at higher temperature the HCC formed in the reaction may
undergo backward reaction due to dissociation at higher
temperature. Similarly it was found that for the N-chlorina-
tion the optimum temperature is 10-15 °C.
of acetic acid lead to an increased reactor size and thereby
increased capital cost and operating cost. Therefore, the
amount of solvent was experimentally optimized, and it was
found that 500 mL of acetic acid for 0.047 mol of 10 were
optimum. At this ratio, the mixing was good and the optimum
yield and purity were obtained.
Effect of pH. In the formation of 11 from 10, as it is
depicted in Schemes 1 and 2, hydrochloric acid is produced
in the first step. Therefore the pH of the reaction decreases
with time. It was experimentally observed that in the
beginning of the reaction the pH was 1.7 and as reaction
progresses towards the forward direction it reduced to 0.41.
The N-chlorination is highly pH sensitive. It is clear from
the mechanism that it takes place through the formation of
hypochlorous acid and hypochloride ion, where the chlorine
bears a slightly positive charge, which must be generated
for the N-chlorination. But at low pH (as in acetic acid) HOCl
dissociates to HCl and nascent oxygen. Positive chlorine will
not be available, and therefore the N-chlorination cannot take
place at a lower pH. It was observed that it takes place at
neutral pH (≈ 7.0).
Effect of Amount of Solvent. In both reactions acetic
acid was used as solvent. It was observed that the amount
of solvent has an influence in the purity of 11 and 1. If too
little of an amount of acetic acid is used, the product was
found to be less pure. This may be attributed to improper
mixing of the reactants. On the other hand larger amounts
Effect of Scavenger of Hydrochloric Acid. The forma-
tion of partial chlorinated products is a problem when the
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Figure 1. Effect of moles of pyridine on purity and yield of
CC-2 obtained from reaction in the presence of pyridine as
catalyst. Conditions: substrate (DPU), 0.045 mol; reaction
temperature in first step, 80-82 °C; reaction temperature in
second step, 10-15 °C; reaction time, 8 h (4 h in first step and
4 h in second step).
Figure 2. Effect of moles of ethylenediamine on purity and
yield of CC-2 obtained from reaction in the presence of
ethylenediamine as catalyst. Conditions: substrate (DPU), 0.045
mol; reaction temperature in first step, 80-82 °C; reaction
temperature in second step, 10-15 °C; reaction time, 8 h (4 h
in first step and 4 h in second step).
reaction is carried out without any scavenger of hydrochloric
acid. On the other hand by performing the reaction in the
presence of a scavenger, complete chlorination takes place
and the conversion towards the desired product is enhanced
and thereby increases the yield of product by restricting
formation of impurities. But, use of Lewis acid catalysts such
as AlCl3 and BF3 offered no advantage in this case. It is
assumed (Scheme 2) that hydrochloric acid is produced in
the reaction, and any compound that acts as a scavenger for
the HCl can shift the reaction towards the completion of
substitution of the aromatic hydrogen. That means the
reaction is shifted in the forward direction. Therefore, the
reaction was studied with the use of pyridine, triethylamine,
ethylenediamine, hexamethylenetetramine, 4,4′-bipyridine,
diethylamine, and dicyclohexylamine, as these are possible
scavengers of HCl. So, these amines are capable of ac-
celerating the aromatic chlorination.
Scheme 4. Mechanism of conversion of 10 to 11 in the
presence of pyridine
The result of reactions carried out in the presence of
different scavengers is tabulated in Table 1. The effect of
different scavengers on purity and yield is shown in Table
1. The same has been shown in graphical form in order to
find out the optimum amount of each scavenger. The result
of reactions carried out with pyridine is shown in Figure 1.
Here the pyridine takes part in the reaction as depicted
through Scheme 4. It is clear that the aromatic chlorination
is facile in this case, since pyridine reacts with the HCl
produced and forms pyridiniumhydrochloride salt, which
ensures the reaction shifts towards the forward direction. This
is also clear from the observation that the pH initially
decreases (due to the formation of HCl) but, after a certain
time, again increases because HCl is consumed for the
formation of pyridiniumhydrochloride salt. From Figure 1
it is clear that as the scavenger-to-substrate ratio increases,
both the yield and purity of the product obtained increase,
attain maxima, and decrease again. It was observed that the
optimum yield and purity of 1 obtained were 80% and 78%,
respectively, and 0.13 mol of pyridine is optimum for 0.045
mol of 10.
observed that, for 0.045 mol of 10, the purity of 1 gradually
increases up to 0.15 mol of ethylenediamine, but the yield
improvement is not appreciable. Similarly the results of the
reactions carried out in the presence of hexamethylenetet-
ramine, bipyridine, dicyclohexylamine, and triethylamine are
shown in Figures 3-6, respectively. In all these cases the
optimum conditions and the yield and purity were obtained.
In the case of selection of a proper scavenger for a
particular process, cost is one of the major criteria along with
its activity or efficiency. Among all the scavengers tried,
hexamethylenetetramine is the cheapest and is available in
solid form. Obviously there is an inclination to use this cheap
material as a scavenger of HCl for conversion of 10 to 11 in
the production of 1. But the main problem is that when the
reaction was carried out in the presence of hexamethylene-
The result of reactions that were carried out with
ethylenediamine as a scavenger is shown in Figure 2. It was
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Figure 6. Effect of moles of triethylamine on purity and yield
of CC-2 obtained from reaction in the presence of triethylamine
as catalyst. Conditions: substrate (DPU), 0.045 mol; reaction
temperature in first step, 80-82 °C; reaction temperature in
second step, 10-15 °C; reaction time, 8 h (4 h in first step and
4 h in second step).
Figure 3. Effect of moles of hexamethylenetetramine on purity
and yield of CC-2 obtained from reaction in the presence of
hexamethylenetetramine as catalyst. Conditions: substrate
(DPU), 0.045 mol; reaction temperature in first step, 80-82
°C; reaction temperature in second step, 10-15 °C; reaction
time, 8 h (4 h in first step and 4 h in second step).
reaction was carried out with dicyclohexylamine, the purity
of the product was very poor and in fact less than that when
the reaction was carried out without a scavenger of HCl.
Good purity product was obtained when the reaction was
carried out in the presence of triethylamine, though the yield
was not appreciable. But 0.045 mol of 10 requires a large
amount of triethylamine (20 mL), which means the reactor
volume requirement will be higher in the case of large scale
production.
Conclusion
Figure 4. Effect of moles of bipyridine on purity and yield of
CC-2 obtained from reaction in the presence of bipyridine as
catalyst. Conditions: substrate (DPU), 0.045 mol; reaction
temperature in first step, 80-82 °C; reaction temperature in
second step, 10-15 °C; reaction time, 8 h (4 h in first step and
4 h in second step).
The conversion of 10 to 1 was studied in the presence of
different homogeneous scavengers of HCl, and a much higher
conversion was obtained in the best case. One of the
coproducts was removed in situ from the reaction mixture,
which forced the forward reaction to go to completion, and
the problem of simultaneous generation of impurities with
the desired product was solved.
It was observed that the presence of pyridine and
ethylenediamine are almost equally effective in the comple-
tion of aromatic chlorination of 10, thereby improving the
yield and purity of the final product.
The effects of pH, temperature, and the amount of solvent
were studied. The optimum conditions for maximum yield
and purity of 1 for different scavengers were obtained.
The result of this study will be of immense help for further
study in this reaction, and it will also help in the scale-up of
the process. The study will also be of value to the design
engineers for designing a plant for the manufacture of 1.
Figure 5. Effect of moles of dicylohexylamine on purity and
yield of CC-2 obtained from reaction in the presence of
dicylohexylamine as catalyst. Conditions: substrate (DPU),
0.045 mol; reaction temperature in first step, 80-82 °C; reaction
temperature in second step, 10-15 °C; reaction time, 8 h (4 h
in first step and 4 h in second step).
Experimental Section
Materials and General Methods. 10 is the main precur-
sor material in the synthesis of 1. 10, synthesis grade, is
obtained from M/s Sigma-Alrich. Acetic acid, sodium
hydroxide, dichloromethane, and hexane (all synthesis
grades) were purchased form M/S Qualigens India Ltd.
Pyridine, triethylamine, ethylenediamine, hexamethylenetet-
ramine, 4,4′-bipyridine, diethylamine, diethylamine, and
dicyclohexylamine (all analytical grade) were purchased from
M/s S.D. Fine Chemicals, India. Acetone and dichlo-
tetramine, it was observed that both the yield and the purity
were very poor. In this case the product mixture in the reactor
also became dark yellow, making the isolation difficult.
Excellent purity product was obtained when bipyridine was
used as a scavenger, but the yield was very poor. When the
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Figure 8. Flow diagram of the process as used for the synthesis
of CC-2.
the pH of the mixture became almost neutral (checked by
pH paper and a pH meter), and chlorine was passed with
continuous stirring. N-chlorination takes place during this
step, which is evident by redissolution of fluffy precipitate
that was formed in the first step. This step requires
approximately 3-4 h. After complete dissolution of the fluffy
precipitate, the passing of chlorine was stopped and the
reaction mixture was poured into ice-cold water. In cold
water, precipitation of CC-2 occurs, which was filtered on a
sintered glass funnel and dried. The pyridiniumhydrochloride
is soluble in water and hence will go with the filtrate making
the separation of the product from the mixture very easy.
The product was analyzed by HPLC and NMR. The complete
flow diagram of the process is shown in Figure 8.
The samples were analyzed using high performance liquid
chromatography (HPLC), (Shimadzu, Japan, model LC-6A)
fitted with a CTO-2A column oven. A UV detector (SPD-
6AV) was used for scanning. µ Porasil (300 × 3.9 mm2)
supplied by M/S Waters, India was used as the column, and
the column temperature was kept at 30 °C. The mobile phase
was a mixture of hexane and dichloromethane (65 to 35),
and the flow rate of the mobile phase was 2 mL/min. The
samples were dissolved and diluted in dichloromethane, and
10 µL were injected into the column through a Reheodyne
injector. Chromatopac (C-R3A) was used as the integrator
and recorder.
Figure 7. Experimental setup for chlorination of diphenylurea
in the presence of different scavengers of hydrochloric acid:
CW, cooling water; H, heating coil; R, reactor; M, motor; I,
impeller.
romethane, used as reagents for analysis on high performance
liquid chromatography (HPLC), were of HPLC grade and
obtained from M/S E. MERCK, India.
The conversion of 10 to 11 and then 1 by chlorination
was studied in a mechanically agitated glass reactor with a
1000 mL capacity. The glass reactor was equipped with a
four-bladed turbine impeller, a thermowell for measuring the
temperature, and a gas inlet tube. A reflux condenser with a
provision for chilled water as a coolant was also mounted
on the reactor to condense and reflux solvent vapors. The
entire setup was immersed in a constant temperature oil bath,
maintained by using a temperature indicator and controller
(TIC). The schematic diagram of the experimental setup is
given in Figure 7.
A measured amount of solvent, acetic acid (500 mL), was
put in the reactor. A weighed quantity of precursor 10 (10
g, 0.045 mol) was added into the reactor. Then the content
of the reactor was heated with constant stirring. When the
temperature of the reaction mixture reached the desired value,
a measured quantity of homogeneous scavenger was added
and passing (bubbling) of chlorine through the liquid was
started. This was considered as zero time. Samples were
taken out at various time intervals during the experiment.
The samples were filtered, and the solid product was
separated from the substrate, scavenger, and the solvent.
These samples were analyzed by NMR and IR.
Future Scope of Work
The kinetics of the reaction will be studied, and the
activation energy, reaction order, and other kinetic parameters
will be found out. The overall rate expression needs to be
found out. The effect of hydrodynamic parameters in the
reaction needs to be studied, and the scale-up parameters
will be found out. The reaction and the process will be
studied in different types of reactors. The complete system
will be modeled, and simulated results will be verified
experimentally.
At this stage, the passing of chlorine was stopped and
reaction mixture was cooled to 5-15 °C in an ice-water
bath. When the temperature of the mixture reached 10 °C,
sodium hydroxide was added and then bubbling of chlorine
gas was again started with constant stirring. Addition of
NaOH was continued in portions at 10-15 min intervals until
Received for review January 4, 2006.
OP060002P
Vol. 10, No. 3, 2006 / Organic Process Research & Development
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