Process Optimization, Product Profile Mapping, and Intensification of 1,1-Diamino-2,2-dinitroethylene

Article abstract of DOI:10.1021/acs.oprd.9b00372

Industrialization of a chemical process needs an understanding of process chemistry, optimal process envelope, and the best choice of operation. 1,1-Diamino-2,2-dinitroethylene (FOX-7) is a new generation, and the highly insensitive compound finds application in high-energy formulations as well as preparation of novel high-energy compounds. The present study highlights efforts made for establishing a continuous process for FOX-7. The intermediates of nitration of 2-methylpyrimidine-4, 6-dione were isolated and characterized by spectroscopic tools. Reaction kinetics was also derived for the formation of intermediates. Product profiles of the reaction were evaluated on deriving expressions for various reactors. The simultaneous effect of heat and reaction was evaluated in a tubular reactor to obtain the runaway reaction condition. The effective reactor scheme was evaluated, designed, and experimented. Process intensification was carried out in a continuous set up comprising various contact patterns. The present study delivered a safe and productive method for FOX-7 processing

Full text of DOI:10.1021/acs.oprd.9b00372

Subscriber access provided by University of Winnipeg Library
Full Paper
Process Optimization, Product Profile Mapping and
Intensification of 1, 1-Diamino-2,2-Dinitroethylene
Pandurang Maruti Jadhav, Sarangapani Radhakrishnan, Rajendra Shivaji Patil, and Raj Kishore Pandey
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00372 • Publication Date (Web): 29 Nov 2019
Downloaded from pubs.acs.org on November 29, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 22
Organic Process Research & Development
1
2
3
4
5
6
Process Optimization, Product Profile Mapping and Intensification of 1,
1-Diamino-2,2-Dinitroethylene
7
8
Pandurang M. Jadhav1* Sarangapani Radhakrishnan1 Rajendra S. Patil2 and Raj K.
,
,
9
Pandey1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1High Energy Materials Research Laboratory, Pune, India
2Advanced Centre of Energetic Materials, Nasik, India
e-mail: jadhav.pm@hemrl.drdo.in
Abstract
Industrialization of a chemical process needs an understanding of process chemistry;
optimal process envelope and the best choice of operation. 1,1-Diamino-2,2-
dinitroethylene (FOX-7) is a new generation, and highly insensitive compound finds
application in high energy formulations as well as preparation of novel high energy
compounds. The present study highlights efforts made for establishing a continuous
process for FOX-7. The intermediates of nitration of 2-methylpyrimidine-4, 6-dione were
isolated and characterized by spectroscopic tools. Reaction kinetics was also derived for
the formation of intermediates. Product profiles of reaction were evaluated on deriving
expressions for various reactors. The simultaneous effect of heat and reaction was
evaluated in a tubular reactor to obtain the runaway reaction condition. Effective reactor
scheme was evaluated, designed and experimented. Process intensification was carried
out in continuous set up comprising various contact patterns. The present study delivered
a safe and productive method for FOX-7 processing.
Keywords: FOX-7, Reaction kinetics, Reactor design, Stability analysis, Process
intensification
1
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 22
1
2
3
4
1. Introduction
5
6
7
8
1,1-Diamino-2,2-dinitroethene (FOX-7) has emerged as an interesting high explosive
compound since its discovery because of its diversified applications. It has a superb
explosive characteristics like high detonation performance, thermal stability, less
sensitivity to impact and friction, etc.1 Hence, it is reported as a potential candidate for
high energy formulations over conventional secondary explosives such as 1,3,5-trinitro-
1,3,5-triazinane (RDX) and 1,3,5,7-tetranitro-1,3,5,7-tetrazoctane (HMX) in view of
comparable performance with enhanced safety.2 Performance characteristics of FOX are
provided in table S1 in supporting information. Ostmark et al.3 reported the compatibility
of FOX-7 with a range of binders (including GAP and HMDI) and the energetic
plasticizers (butyl-NENA and K-10) which indicated its applicability in various high
energy formulations. Stability of FOX-7 with TNT encouraged its usage in polymer
bonded explosives (PBX).4 FOX-7 and HMX containing PBX formulations showed
better mechanical properties as well as comparable performance characteristics in
comparison with RDX based PBX.5 Moreover, FOX-7 containing shaped charges showed
better characteristics of the cumulative jet as well as its penetration ability better than
Hexotol (60% RDX and 40% TNT) charges.6 Application of FOX-7 in aluminized
composite propellant was found to be promising as FOX-7 decreased detonation
properties of propellant without compromising performance characteristics.7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In addition, the “push-pull” effect in FOX-7 structure due to the presence of electron-
donating amino groups and electron-withdrawing nitro groups on adjacent carbons has
attracted great attention amongst academic and industrial chemists. Several derivatives of
FOX-7 have been reported over the last five years which were obtained by condensation,
halogenation, nitration, acid-base reactions, and coordination reactions.8 FOX-7 is found
as a superb precursor to acyclic or cyclic compounds; hence it has become important to
synthetic chemistry community in the development and applications of its new
derivatives. Study of the metals with FOX-7 highlights its features as a potential ligand or
an anionic species.9 Halogen, hydrazine and polynitro derivatives of FOX-7 are of great
interest in energetic materials community as the products are found to be rich in energy
content.10 Some of the halogenated and polynitro derivatives of FOX-7 are yielded as
oxygen-rich species and found application in propellant formulations.11
2
ACS Paragon Plus Environment

Page 3 of 22
Organic Process Research & Development
1
2
3
4
5
6
Thus, FOX-7 is a highly important compound for academic, industrial chemists and
energetic community. Its diversified application in various fields demands process
intensification study to meet the requirement in a huge way.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2. Synthesis routes of FOX-7
FOX-7 has a relatively simple molecular structure, while the chemical precursor to
synthesize FOX-7 has been known for many years but obtaining the two amino groups on
an ethene is difficult with straightforward synthetic techniques. A more complex
nitrogen-containing heterocyclic ring is first nitrated, and then the ring is broken, forming
both of the amines and the double bond to ethane. The different routes of FOX-7
synthesis are discussed below.
2.1 Route 1: Latypov et al. reported synthesis of FOX-7 from the nitration of 2-
methylimidazole at a controlled temperature (15-20°C).1a 2-Dinitromethylene-5,5-dinitro-
imidazolidin-4-one is one of the key intermediates (Figure 1) of the reaction which loses
nitrogen oxides to obtain 2-dinitromethylene-imidazolidne-4,5-dione, which further
dissolved in aqueous ammonia to yield bright yellow solid (FOX-7) with an overall yield
of about 13%. Applicability of this route is limited due to temperature sensitive nature of
reaction, formation of nitroformate and parabamic acid as byproducts, product
contamination due to oxamide and low yield.
NO2
H
N
H
N
O
O N
2
NH
NH
O2N
O2N
O2N
O2N
N
2
COO-
COO-
NO2
CONH2
CONH2
HNO3 / H2SO4
15 -20 o
aq. NH3
H3C
+
2
+
-N2O3
C
N
H
N
H
O N
2
N
H
O
O
2-methyl imidazole
FOX-7
2-(dinitromethylene)imidazolidine-4,5-dione
+
NO2
HNO3 / H2SO4
H
N
O
O
C-
NO2
45 - 50 O
C
O
NO2
N
H
Parabamic acid
Figure 1. Reaction scheme for route 1: Nitration of 2-methylimidazole
3
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 22
1
2
3
4
5
6
7
8
9
2.2 Route 2: In this route (Figure 2), nitration of 2-methoxy-2-methyl-4,5-
imidazolidinedione and /or 2-methyl-4,5-imidazolidinedione gives 2-dinitromethylene-
imidazolidine-4,5-dione.12 Henceforth ammonolysis path follows same as route 1 to yield
FOX-7. However, process becomes unfeasible due cumbersome and inconvenient way of
synthesizing starting materials, usage of dry HCl gas and product contamination.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
N
O
H3CO
H
N
H3C
O
H2N
O N
2
NH
NH
N
H
O2N
O2N
COOC2H5
COOC2H5
2
COO-
COO-
O
O
HNO3/ H2SO4
< 35 o
aq. NH3
MeOH/Na
Dry HCl
CH3
+
+
2
+
C
H
N
ClH2N
N
H
O N
2
O
FOX - 7
2-(dinitromethylene)imidazolidine-4,5-dione
H3C
N
H
+
O
NO2
C-
NO2
NO2
Figure 2. Reaction scheme for Route 2: Nitration of 2-methoxy-2-methyl-4,5-
imidazolidinedione and /or 2-methyl-4,5-imidazolidinedione
2.3 Route 3: Astrat'ev et al.13 reported synthesis of FOX-7 from nitration of 2-methyl-
pyrimidine-4,6-dione in mixed acids at about 5 °C and followed by hydrolysis of 2-
dinitromethylene-5,5-dinitro-dihydro-pyrimidine-4,6-dione (Figure 3). 2-Methyl-
pyrimidine-4,6-dione is easily prepared from acetamidine hydrochloride and diethyl
malonate in contrast to starting materials of above route. The overall yield of FOX-7
from of 2-methyl-pyrimidine-4, 6-dione is 80%.
O2N
NO2
O
O
NO2
NO2
O
O
O N
NH
2
2
OH-, hydrolysis
-CO2
HNO3(exc)
H2SO4
HC-
+
N
NH
HN
NH
O N
NH
2
2
FOX - 7
(6)
(5)
CH3
O2N
NO2
NO2
2-methylpyrimidine-4,6-dione
+
(1)
NO2
C-
NO2
Figure 3. Reaction scheme for Route 3: Nitration of 2-methyl-pyrimidine-4,6-dione
4
ACS Paragon Plus Environment

Page 5 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
In view of improvisation of FOX-7 synthesis, attempts were made by researchers on
considering various precursors mainly 6-methyl-1,3,5-triazine-2,4-dione and 2,4-
dimethoxy-6-methyl-1,3,5-triazine.14 However, encouraging results were not obtained.
Thus, the nitration of 2-methyl-pyrimidine-4,6-dione is found to be suitable and
productive route for the production of FOX-7 on a larger scale, hence adopted for
intensification studies.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. Process chemistry of 2-methyl-pyrimidine-4,6-dione nitration
Process chemistry has a profound role in the scale-up. To successfully scale-up of any
chemical process, it is necessary to understand the reaction mechanisms. Influence of
each reaction parameters on the overall process should be clearly understood before
going for the scale-up as it is useful in designing the equipment, and operating methods.
Synthesis of FOX-7 involves the successive nitration on the pyrimidine ring followed by
hydrolysis. Figure 3 indicates that FOX-7 synthesis is achievable only after formation of
5. Nitration of 2-methyl 4,6-dihydroxy pyrimidine is believed to be a sequential attack of
nitronium ions at an active methylene site and the methyl side chain. 14b, 15 The expected
reaction scheme is shown in Figure 4.
2
2
HO
OH
O
O
O
OH
HO
OH
1 eq HNO 3
N
N
N
N
N
N
N
N
H
CH3
CH3
(1)
CH3
CH3
(2)
1 eq HNO 3
O2N NO2
O2N NO2
O2N NO2
O2N NO2
O
O
O
OH
O
OH
O
OH
1 eq HNO 3
1 eq HNO 3
HN
O2N
N
HN
N
HN
N
H
N
N
CH3
(3)
NO2
H
NO2
H
H
(4)
O2N NO2
O2N NO2
O
O
HO
OH
HN
O2N
NH
NO2
N
N
O2N
(5)
NO2
Figure 4. Reaction mechanism for the formation of mono, di, tri and tetra nitro
derivatives of 2-methyl 4, 6-dihydroxy pyrimidine
5
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 22
1
2
3
4
5
6
7
8
9
The nitronium ion preferentially would attack the 5th position of 2-methyl-pyrimidine-
4,6-dione since it possesses an active methylene group. This is supposed to be the fast
reaction and yields the mono nitro derivative of 2-methyl 4, 6-dihydroxy pyrimidine (2).
However, further nitronium ion attack would be unfavorable at 5th position of 4,6
dihydroxy 2-methyl-5-nitro pyrimidine due to the destruction of the aromatic system (in
3), hence, this process is expected to be slow. These mechanisms for the formation of 2
and 3 reveal the scope of series reactions with different reaction pace. Figure 4 also
shows the mechanism involved in the formation of 6-hydroxy-2-methyl-5,5-
dinitropyrimidine-4(5H)-one (3). Further, the introduction of nitro group on the methyl
group of 3 would yield trinitro-derivative of 1. This reaction may be relatively faster than
the formation of 3. Figure 4 illustrates the expected mechanism for formation of (2Z)-6-
hydroxy-5,5-dinitro-2-(nitromethylidene)-2,5-dihydropyrimidin-4(3H)-one. Figure 4 also
indicates the mechanism for the formation of 2-(dinitromethylidene)-5,5-dinitro-2,5-
dihydropyrimidine-4,6-diol on a further attack of the nitro group on 4. Thus the
mechanism supports that nitration of 2-methyl 4, 6-dihydroxy pyrimidine is sequential
steps where the formation of intermediates plays a vital role in deciding the reaction
profile for the desired product. Moreover, it demands special treatment for a selection of
contact patterns in view of maintaining higher product profile as well as reaction pace. In
the present study, intermediates 2, 3, 4 and 5 were isolated from a reaction and studied to
determine their nature as well rate of formation. The derived information was utilized for
designing of contact pattern and established a continuous process for FOX-7 production.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. Experimental and characterization details
2-Methyl 4,6-dihydroxy pyrimidine (50 g) was dissolved in concentrated (98% wt.)
sulfuric acid (225 ml) in a cylindrical jacketed glass reactor. This feedstock was used for
the synthesis of 2, 4 and 5 compounds while 3 was prepared from 2. The obtained
products were characterized by spectroscopic, chromatographic techniques, and thermal
analysis. The IR spectra were recorded on PerkinElmer FTIR-1600 spectrophotometer in
KBr matrix and 1H NMR spectra scanned on a 300 MHz Varian instrument in deuterated
dimethyl sulfoxide at 30 C with TMS as an internal standard. The DSC studies were
undertaken on a PerkinElmer DSC-7 instrument at the heating rate of 10 C/min.
6
ACS Paragon Plus Environment

Page 7 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Chromatographic analyses were carried out on Waters Alliance HPLC system equipped
with an autosampler and UV-Visible absorbance detector. Isocratic elution was
performed using 3.9 x 150mm Novapak C18 (4m) column with a mixture of methanol
and water (40:60) as eluent. Figure S1 in supporting information shows combined spectra
of HPLC analysis of 2, 3, 4, 5, and 6.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.1 Synthesis of 2
One equivalent of fuming nitric acid (98% wt.) was added to 20 ml feedstock solution (4
gm of 1). The reaction was allowed to proceed at isothermal conditions under constant
agitation. The reaction mass was quenched in ice water (90 ml) at a different time interval
to obtain the extent of reaction. The product was filtered, water washed, dried, and
weighed.
4.2 Synthesis of 3
One equivalent of fuming nitric acid (98% wt.) was added to 20 ml feedstock solution (4
gm of 2). The above-said procedure was followed for isolation and characterization of 3.
The pure 3 was obtained after performing the reaction in a tubular reactor.
4.3 Synthesis of 4 and 5
3 was nitrated with both one and two equivalence of fuming nitric acid (98% wt.). The
reaction mass was isolated in methanol as well as chloroform to obtain 4 and 5. Further,
the formation of 4 and 5 was also carried out on the addition of three and four equivalents
of fuming nitric acid (98% wt.) to 1 respectively.
The above experiments were also carried out at a different temperature ranges from 15 to
35oC at the increment of 10oC for kinetics determination.
5. Result and Discussion
Preparation of FOX-7 involves the series of nitration reactions followed by hydrolysis.
Formation of the intermediate is vital for these types of reactions where the mixing of
fluid of different compositions is involved. The maximum possible amount of
intermediates is obtained if fluids of different concentrations and at different stages are
not allowed to mix.16 For series reactions, more intention has always given to maximize
intermediates for achieving a higher yield of the final product. The absolute information
7
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 22
1
2
3
4
5
6
on rates of formation and disappearance of intermediates facilitate to opt for the best
reaction system. On the same line, the present work performed to obtain data on the
reactive behavior of intermediates of 1 and is as follows;
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.1 Nitration of 1 to 2
On addition of one equivalent of fuming nitric acid (98% wt.) in the presence of sulfuric
acid to 1 gives 2 which was characterized by spectroscopic tools. Figure S2 and S3 show
1H NMR and 13C NMR spectra respectively which confirm the identity of 1. Structure of
2 was confirmed from the peaks in IR spectra for NH2 (3408 & 3330 cm-1) and NO2
(1520 & 1472 cm-1) groups and peaks in 13C NMR at δ 158 (C-NO2) and δ 128 (C-NH2).
DSC of 2 showed decomposition peak at 296ºC with a heat release of 1188.4 J/g which
was different than 1 and 6. Impact insensitivity analysis showed that 2 is highly
insensitive and could not explode on the impact of 2 kg mass up to 170 cm and 36 kg of
friction.
Further, a study on the rate of formation of 2 at 15, 25 and 35oC revealed that the
formation of 2 decreases with increasing temperature in the batch reactor. Table 1 shows
that reaction extent at various temperatures. The conversion towards 3 and further to 6
was observed at a higher temperature even addition of one equivalent of fuming nitric
acid (98% wt.). This indicates that the rate of intermediates formation are comparable and
cannot be controllable unless proper contact of reaction entities. The time required for
complete conversion at low temperature was more than 1.5 hours. The higher conversion
of 2 from rate equation was expected by increasing the concentration of nitric acid in the
reactor. This could not achieve as reaction proceeds further to the formation of 3, 4 and 5
in a batch reactor.
Table1: Product distribution based on temperature and nitric acid quantity
Reaction temp.
(K)
Nitric acid
equivalence
Reaction path
Product
constituents
% Yield
288
298
1
1
1 - 2
1 - 2
2
2
55
67
8
ACS Paragon Plus Environment

Page 9 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
308
298
288
298
298
298
298
1
1- 2
1 - 2
2 - 3
2 – 3
2 – 3*
1 – 4
1 - 5
2 and 3
50
19
55
50
15
-
2.5
1
2, 3 and 6
2 and 3
2 and 3
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
3
4, 5 and 6
4, 5 and 6
4
-
* Reaction in a tubular reactor
- Yield of 4 and 5 could not realize separately due to their pyrophoric nature and
analogous spectroscopic characteristics.
Reaction kinetics was evaluated for nitration of 1 on the addition of equivalence of
fuming nitric acid at 288, 298 and 308 K. The decay in the concentration of 1 was
monitored on isolation of reaction mass fixed interval of time (stopped flow analogy).17
The results are depicted in Figure 5.
1.4
298K
288K
1.2
1
0.8
0.6
0.4
0
10
20
30
40
50
60
Time (min)
Figure 5. C-t profile of 1 during the formation of 2
9
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 22
1
2
3
4
5
6
7
8
9
This shows that the complete conversion of 1 for 2 is not obtained even at 60 minutes,
indicating the slow nature of reaction with less energy-intensive characterization. Overall,
reaction kinetics was found to be second-order denoting first order with respect to 1 and
nitric acid. Arrhenius parameters were governed for the formation of 2 and confirmed
that the slow pace of reaction with less activation energy. Kinetics parameters are
tabulated in Table 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2: Kinetics for nitration of 1 (Rate constants units: mol/lit and min.)
Reaction step Rate expression k288
k298
k308
Ea, kcal/mol
12.74
1-2
2-3
3-5
-r1=k1C1CHNO3
-r2=k2C2CHNO3
-r3=k3C3
0.0210
0.0051
0.0085
0.0450
0.0136
0.0130
0.091
0.034
0.021
16.83
7.90
5.2 Nitration of 2 to 3
In series reaction, intermediates form sequentially in the presence of excess reagents and
intermediates. This situation is valid when the rates of each step are comparable. The
similar observations were noticed when 2 was nitrated under various temperatures and
prolonged period on the addition of one equivalent of fuming nitric acid in a batch
reactor. In all cases, it was found that reaction proceeded further and yielded in 4 and 5.
This restricts isolation of 3 to obtain it in pure form. This was overruled by modifying the
contact pattern and preparation method. The product obtained from a tubular reactor was
analyzed and found to contain small traces of 2 in a higher content of 3. Further, it was
purified by leaching them for several instances in methanol. Purified 3 was characterized
by spectroscopic tools. Figure S1 shows a single peak of 3, which was found different
13
than 2 and 6. IR and C NMR spectra of 3 showed spectra analogous to that of 2. This
was due to attachment same functional group (nitro) on the same carbon atom (5th
position of carbon in the ring). However, 1H NMR spectrum and decomposition of 3 was
different than 2. Figure S4 shows that the absence of hydrogen peak at 13.31 ppm in
1
comparison with the H NMR spectrum of 2 as shown in Figure S2. This confirms the
10
ACS Paragon Plus Environment

Page 11 of 22
Organic Process Research & Development
1
2
3
4
5
6
formation of 3 due to the replacement of hydrogen from the 5th position of 2 by the nitro
group.
Figure S5 shows that decomposition of 3 at 252ºC with a heat release of 134 J/g in DSC
analysis which was different than the 2 and 6. This confirmed the formation of 3 from 2
under controlled nitration conditions. The impact sensitivity (h50) and figure of the
insensitivity of 3 were found about 60 cm and 71 respectively; however, it was not shown
stimulus at 36 kg friction. Reaction kinetics for the formation of 3 was derived and
tabulated in Table 2. The formation of 3 plays an important role in deciding the yield and
purity of FOX-7 as it is a slower step than other steps. Hence it is necessary to improve
its processing to increase the productivity of the process.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.3 Formation of 4 and 5:
The formations of 4 and 5 were expected on the addition of one and two equivalence of
fuming nitric acid to 3 respectively. However, both the samples have shown almost
similar HPLC spectra (figure S1). This indicated that the formation of 4 and 5 take place
simultaneously. With this, reaction kinetics were derived considering single step and
outcome provided in table 2. The rate of formation of 5 was found to be slow in
comparison with other steps. However, their formation possesses lower activation energy.
This indicates that formation of 5 is feasible even at low energy barrier. Caution:
Compounds 4 and 5 are pyrophoric. Compounds are catching fire in the absence of acid
and at about 50oC. Hence, these compounds shall be handled with special precautions.
5.4 Effect of contact patterns on the product profile
Industrialization of a chemical process needs an understanding of process chemistry;
optimal process envelope and the best choice of operation. Selection of mode of
operation for scale-up of processes is a combination of science and art. Chemical Process
can be conducted in batch, semi-batch, or continuous mode of operation. Understanding
of reaction and its mechanism is mandatory in this regard. It gives an idea about the
suitability of mode of operation and reactor (contact pattern). The above study pertaining
to isolation and characterization of intermediates of FOX-7 synthesis from the nitration of
11
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 22
1
2
3
4
5
6
7
8
9
2-methyl 4, 6-dihydroxy pyrimidine (figure 3) confirms the multiple series reactions
nature of the process. In series reaction, it is known that the formation of intermediates
plays a vital role in deciding the reaction profile for the desired product due to the
involvement of mixing of fluids of different concentrations.18 Maximum possible
amounts of intermediates are required to achieve a higher yield of the final product. Here,
reaction kinetics of this process as tabulated in table 2 shows that the least activation
energy belongs to the formation of 4 and 5. This indicates that formation of 4 and 5 will
be favored as soon as 3 is available in a reactor. Hence, the concentration of 3 will be
almost negligible during the reaction in comparison with concentrations of 2, 4 and 5.
This condition is likely to affect on yield as well as purity of 6. Hence, any instance the
concentrations of intermediates have to be increased to obtain the higher yield and purity
of 6. Selection of the best contact pattern (reactors) is essential here to achieve higher
concentrations of intermediates. Batch mode is usually preferred for small scale
production because it is a relatively simple device and needs small auxiliary equipment or
instrumentation. Hence, initial concentrations of intermediates were evaluated in a batch
reactor. Table 2 shows the three independent reactions and their kinetics. Thus, it is
essential to govern a single rate expression in terms of concentration of 1. The rate
expressions and their rate constants are as follows;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1)
(2)
(3)
푟1 = ― 푘1 ∗ 퐶1 ∗ 퐶
퐻푁푂3
푟2 = 푘1 ∗ 퐶1 ∗ 퐶
― 푘2 ∗ 퐶2 ∗ 퐶
퐻푁푂3
퐻푁푂3
푟3 = 푘1 ∗ 퐶1 ∗ 퐶퐻푁푂 + 푘2 ∗ 퐶2 ∗ 퐶퐻푁푂 ― 푘3 ∗ 퐶3
3
3
(4)
푟5 = 푘3 ∗ 퐶3
Equation one can be solved for the equimolar concentration of 1 and nitric acid and
solution is as follows;
퐶0
(5)
퐶1 = (
)
퐶0푘1푡 + 1
Where, C0 is initial concentration of 1 and t is reaction time.
On substituting eq. 5 in eq. 2 for solving C2 for equimolar concentration, it becomes,
2
푑퐶2
푑푡
퐶0
( )2
+ 푘2 ∗ 퐶2 = 푘 ∗
(6)
(
(
)
1
)
퐶0푘1푡 + 1
Where, eq. 6 is found to be in the form of Riccati differential equation19 which can be
solved by quadrature to obtain the solution.
12
ACS Paragon Plus Environment

Page 13 of 22
Organic Process Research & Development
1
2
3
4
5
6
7
8
2
(
(
)
)
(
)
(
푘퐶0푘2
1 + 퐶0푘2푡 (퐴 + 1) ― 1
)
)
(7)
퐶2 = (
(퐴 + 2)
2
2
(
)
(
)
(
)
)
(
(
퐶0푘2 퐶0푘2푡 + 1 +
푘1푘 1 + 퐶0푘2푡
)
(
―
(
퐶20푘22
2푘1
)
+ 4퐶20푘1푘2
)
)
푘 = (
퐴 =
― 푘2퐶0
2푘푘1
퐶0푘2
Where,
and
9
Substituting equation 5 and 7 for C1 and C2 respectively in equation 3, equation can be
deduced in the form of Co and C3 analogous to equation 6. However, this differential
equation for C3 becomes very complex due to the involvement of two independent terms
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
of Co. The derived form of C3 is as follows;
―푘3푡
(
)
퐶3 = 푒
―푘
3
(
1 + 퐶 푘 푡)
0 1
― 푘
3
퐶
푘
0 1
(
)
푘3
푘3
푘3
푘3
퐶
푘
―푒
0 1
(
(
)
)
(
)
(
)
(
1
퐶 + 퐶0푒
+
푙표푔 1 + 퐶0푘2푡
+
1 + 퐶 푘 푡 + [0.25]
1 + 퐶0푘1푡
(
)
(
)
(
)(
0 1
{
}
1 + 퐶0푘1푡
퐶0푘
퐶0푘1
퐶0푘1
퐶0푘
(
(
(
(8)
― 푘
― 푘
3
3
(
퐶
)
푘3
푘32
푒퐶0푘
―
―
0푘
1
1
Where,
퐶 = 퐶0푒
2
2
(
)
(
)
(
(
)
퐶0푘
4퐶0푘1
)
1
Finally, the concentration of C5 was obtained from the above equations. These
concentration profiles were evaluated in a batch reactor at 20oC and outcome is plotted in
figure 6.
1.4
1.2
C1
C2
C3
1
C1
0.8
0.6
C3
0.4
0.2
C2
0
0
50
100
150
200
250
300
Time (min)
13
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 22
1
2
3
4
Figure 6. Concentration profile in the batch reactor
5
6
7
8
Figure 6 shows the outcome of batch reactor analysis. This indicates that the formation of
mono (2) and dinitro (3) derivatives are comparable at initial stages and significant decay
in mononitro (2) derivative at the later course of reaction.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
On the other hand, C-t analysis was carried out in PFR, and CSTR and outcome are
shown in figure 7 which was derived on governing equations of concentration in CSTR
as follows.
―2
+ 4 푘1휏 ―1퐶0
―1
(
푘1휏
+
)
(
)
)
퐶1 = (
푘1휏
(9)
(10)
(11)
2
푘2휏 ―2 + 4푘1푘2 ―1퐶1
―1
2
(
+
)
)
퐶2 = (
퐶3 = (
푘2휏
2
2
푘1퐶12 + 푘2퐶2
푘3휏 + 1
휏
)
1
______ PFR
.............. CSTR
0.9
C1
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
C2
C3
C3
C2
0
50
100
150
Time (min)
200
250
300
Figure 7. Concentration profile in plug flow and continuous stirred tank reactors
Slow decay of concentration of 1 was observed in CSTR in comparison with PFR. The
concentration of 3 was found to be higher in PFR than CSTR. This analysis showed that
14
ACS Paragon Plus Environment

Page 15 of 22
Organic Process Research & Development
1
2
3
4
5
6
the single contact pattern is insufficient to meet the desired concentrations of
intermediates in a reactor.
7
8
9
5.5 Reactor configuration and stability analysis
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The above studies of reaction kinetics and product distribution suggest that the batch and
mixed flow reactors are diverting the reaction course as well as yielding lower
concentrations of intermediates which hamper final productivity. Hence, the application
of plug flow reactors is vital to maintain the higher concentrations of intermediates.
Moreover, the plug flow reactor facilitates in altering reaction pace of slow step on
enhancing reaction temperature, here especially for the formation of 3. Overall, the
formation of 2 and 3 is essential in the tubular reactor due to reaction kinetics and
achieving higher yield of the reaction. In contrast, the plug flow reactor offers a variation
in reaction rate along its length. This also affects on isothermal conditions of the reaction.
It has been found that the tubular reactor may exhibit multiple temperatures and
concentration profiles along its axis when an exothermic chemical reaction is
performed.20 Hence, it is essential to obtain the temperature profile of the tubular reactor
along its length. This also helps in showing the runaway condition of reaction. Here,
countercurrent flow of coolant is considered to maintain the outlet temperature reaction
mass within a favorable range for maximization of nitronium ions formation. Heat and
mass balance equations for the plug flow reactor were clubbed to evaluate the
simultaneous effect on temperature and concentration during reaction for formation of 2
along the length of reactor.
Thermal energy balance for reactive fluid within the inner tube:
푑푇푅
푑푡
2푈푖푛
( ) ( )
푇푐표표푙 ― 푇푅 + ―∆퐻푅 푟퐴
푅푖푛
(12)
휌푅퐶푝푅
=
Thermal energy balance for cooling fluid:
푘2
푑푇푐표표푙
푑푡
2푈푖푛
( )
푇푅 ― 푇푐표표푙
푅푖푛 1 ― 푘
(13)
휌푐표표푙퐶푝푐표표푙
=
2
Where, U is overall heat transfer coefficient which derived by standard analogies, R
radius of the tube, T is temperature, cool is coolant, ρ is density, k is radius ratio and HR
is the heat of reaction. The profiles of heat generation and removal along the length of
reactor were generated for various temperatures ranges of feed as well as a coolant fluid.
15
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 22
1
2
3
4
5
6
7
8
340
330
320
310
300
290
280
270
1.00
275K
290K
280K
1.00
300K
0.99
9
0.99
0.98
0.98
0.97
0.97
0.96
0.96
0.95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
275K
280K
290K
300K
0
100
Length (mm)
200
300
270
290
310
T(K)
330
(a)
(b)
Figure 8. (a) Temperature variation profile along the length and (b) actual
conversion profile
The effect of coolant temperature on reaction temperature was evaluated. The selected
coolant temperatures were 275, 280, 290 and 300K. It was desired to control the reaction
temperature at 285K. The observed profiles are shown in figure 8(a). This clearly showed
that reaction temperature varies along the length of the reactor. The maximum reaction
temperature was found to be near the exit end of the reactor. The outlet temperature of
the reactor was found to be close to the coolant temperature. It was inferred that coolant
temperature beyond the feed temperature is not able to withdraw the heat of reaction and
leads to runway condition. Alternatively, the conversion profile against the coolant
temperature was evaluated and shown in figure 8(b). This shows that the sudden rise in
conversion level near the exit end of reactor where a rise in temperature was noticed. The
conversion level after that remains constant as the maximum conversion is achieved in
that region. The sharp rise in conversion level was obtained using coolant temperature
than feed temperature. This indicates the runway condition of reaction for these coolant
temperatures. The analysis helped in identifying the temperature control ability of
selected hardware and runway condition of reaction. The analysis also revealed the
appropriate range of coolant temperature to control the runway condition of reaction.
16
ACS Paragon Plus Environment

Page 17 of 22
Organic Process Research & Development
1
2
3
4
5.6 Process intensification in continuous set-up
5
6
7
With this, two different sizes PFRs followed by a CSTR is formulated for processing of
FOX-7 in continuous mode. The reactor scheme is shown in figure 9.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 9. Reactor scheme for FOX-7 processing in the continuous mode
Here, plant capacity is considered to be 60g/hr of 2-methyl-pyrimidine-4,6-dione. A
solution of 2-methyl 4, 6-dihydroxy pyrimidine (1) and concentrated sulfuric acid was
prepared as a stock solution. A solution was prepared at elevated temperature to minimize
the processing time. The mixture of 1 was to be added to 1st PFR along with only an
equivalent of fuming nitric acid. Coolant was introduced in a jacket of PFR in
countercurrent flow manner. The residence time was varied from 20 to 45 minutes. An
outlet of 2 was mixed with another equivalent of fuming nitric acid in pre-mixer before
entering to 2nd PFR. Reaction pace was increased by circulating water of ambient
condition in the jacket of reactor. Another part of fuming nitric acid and outlet of 2nd PFR
were continuously fed to CSTR. The reaction was controlled at the isothermal condition
in CSTR by circulating coolant in its jacket. A slurry of CSTR was quenched in ice-cold
water continuously. Solids were washed, filtered and dried to obtain FOX-7 at about 75%
yield. The reaction was completed within 120 minutes; thus an improvement in
17
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 22
1
2
3
4
5
6
7
8
9
productivity was achieved. This technology requires low inventory and a higher degree of
safety. These characteristics convey high prospective for scaling of this technology
because of meeting the production requirement of FOX-7 for its direct application in HE
formulation as well as for the preparation of other novel HEMs.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6. Conclusions
There is dire need to establish an effective and safe processing technology for FOX-7 to
cope with the future requirement. 2-Methyl 4, 6-dihydroxy pyrimidine (1) based route for
FOX-7 synthesis is found to be the adaptive as well as productive. Isolation of mono, di,
tri and tetra nitro derivatives of 2-methyl-4, 6-dihydroxy pyrimidine is challenging and
needs special treatment. Isolation of 6-hydroxy-2-methyl-5,5-dinitropyrimidine-4(5H)-
one (3) in a large extent is possible in only tubular reactor. Tri and tetra nitro derivatives
of 1 are found to be pyrophoric in dry condition. In a batch reactor, formation of 4, 6-
dihydroxy-2-methyl-5-nitro pyrimidine (2) increases till 298K and decreases thereafter.
Reaction kinetics supports the formation of tri and tetra nitro derivatives of 1 at low
temperature in batch reactor even on a limited supply of fuming nitric acid. Product
profile in various reactors showed that the batch reactor, as well as single mixed flow
reactor, is not appropriate to maintain the intermediate concentration at a high level.
Application of plug flow reactors for formation of 2 and 3 is vital to obtain a higher
reaction rate as well as yield. Tubular reactor stability analysis indicated the runaway
condition of reaction in case of circulating jacket fluid of more than 300K. Based on
these results, the continuous plant comprising two tubular reactors followed by a mixed
flow reactor is found to be appropriate for processing of FOX-7 in a safe, efficient, and
productive manner. Overall, this study finds efficacy for scaling of FOX-7 process at
higher production capacity level to deal with the requirement of its application in high
energy formations as well as in the preparation of its novel derivatives.
7. Acknowledgment
Authors are thankful to Director HEMRL for granting permission to publish this work.
8. Supporting Information
18
ACS Paragon Plus Environment

Page 19 of 22
Organic Process Research & Development
1
2
3
4
5
6
Comparison of performance characteristics of FOX-7 with conventional explosives and
copies of HPLC spectra of 2, 3, 4, 5 and 6, 1H NMR spectra of 2 and 3, 13C NMR spectra
of 2 and DSC profile 3.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9. References
1.
(a) Latypov, N. V.; Bergman, J.; Langlet, A.; Wellmar, U.; Bemm, U. Synthesis
and Reactions of 1, 1-Diamino-2, 2-Dinitroethylene, Tetrahedron 1998, 54(38), 11525-
11536; (b) Trzciński, W. A.; Cudziło, S.; Chyłek, Z.; Szymańczyk, L. Detonation
Properties of 1, 1-Diamino-2, 2-Dinitroethene (DADNE), J. Hazard. 2008, 157(2-3),
605-612.
2.
2-Dinitroethene (FOX-7), J. Chem. Phys. 2014, 141(13), 134315-1-9.
3. Ostmark, H.; Langlet, A.; Bergman, H.; Wingborg, N.; Wellmar, U.; Bemm, U. In
Booth, R. S.; Butler, L. J. Thermal Decomposition Pathways for 1, 1-Diamino-2,
FOX-7 -a New Explosive with Low Sensitivity and High Performance, 11th International
Symposium on Detonation, Snowmass, CO, USA, 1998¸ 31, 04.09.
4.
Lochert, I. J. FOX-7 -a New Insensitive Explosive, Defence Science And
Technology Organisation Victoria (Australia) Aeronautical and Maritime Research Lab.
2001, DSTO/AMRL-TR-1238.
5.
Thermal Behavior of FOX-7-Based Explosives, J. Energ. Mater. 2013, 31 (1), 72-85.
6. Helte, A.; Carlsson, T. E.; Eldsäter, C.; Lundgren, J.; Örnhed, H. In Performance
Trzciński, W.; Cudziło, S.; Chyłek, Z.; Szymańczyk, L. Detonation Properties and
of FOX-7 (1, 1-diamino-2, 2-dinitroethylene) in Shaped Charge Applications, 23rd
International Symposium on Ballistics, Tarragona, 2007.
7.
Containing HMX and FOX-7, Cent. Eur. J. Energ. Mat. 2008, 5(3-4), 103-111.
8. (a) Gao, H.; Jean'ne, M. S. Recent Progress in Taming FOX-7 (1, 1-Diamino-2, 2-
Florczak, B. A Comparison of Properties of Aluminized Composite Propellants
Dinitroethene), RSC Adv. 2016, 6(61), 56271-56277; (b) Yan, C.; Qi, X.; Wang, K.; Jin,
Y.; Cheng, G.; Liu, T.; Yang, H.; Zhang, Q. Revisiting the Reactive Chemistry of FOX-
7: Cyclization of FOX-7 Affords Fused-Ring Polynitro Compounds, Chem Comm. 2019,
55(24), 3497-3500.
19
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 22
1
2
3
4
9.
(a) Vo, T. T.; Parrish, D. A.; Shreeve, J. n. M. 1, 1-Diamino-2, 2-Dintroethene
5
6
7
8
(FOX-7) in Copper and Nickel Diamine Complexes and Copper FOX-7, Inorg. Chem.
2012, 51(3), 1963-1968; (b) Xu, Y.; Wang, P.; Lin, Q.; Du, Y.; Lu, M. Cationic and
Anionic Energetic Materials Based on a New Amphotère, Sci. China Mater. 2019, 62(5),
751-758.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10.
Vo, T. T.; Jean'ne, M. S. 1, 1-Diamino-2, 2-dinitroethene (FOX-7) and 1-Amino-
1-Hydrazino-2, 2-Dinitroethene (HFOX) as Amphotères: Bases with Strong Acids, J.
Mater. Chem. 2015, 3(16), 8756-8763.
11.
(a) Vo, T. T.; Parrish, D. A.; Shreeve, J. n. M. Tetranitroacetimidic Acid: A High
Oxygen Oxidizer and Potential Replacement for Ammonium Perchlorate, J Am Chem
Soc. 2014, 136(34), 11934-11937; (b) Zhang, J.; Shreeve, J. n. M. 3, 3′-Dinitroamino-4,
4′-Azoxyfurazan and its Derivatives: an Assembly of Diverse N–O Building Blocks for
High-Performance Energetic Materials, J Am Chem Soc. 2014, 136(11), 4437-4445; (c)
Jadhav, P. M.; Prasanth, H.; Pandey, R. K.; Patil, R. S.; Bhattacharyya, S. C. Process
Development, Friction Insensitivity Improvement and Compatibility Studies of
Tetranitroacetimidic Acid, RSC Adv. 2017, 7(49), 30663-30672.
12.
Symposium. Bordeaux, France 2001, 2, 755.
13. Astrat'ev, A.; Dashko, D.; Mershin, A. Y.; Stepanov, A.; Urazgil'deev, N. Some
Bemm, U.; Eriksson, L. Insensitive Munitions & Energetic Materials Technology
Specific Features of Acid Nitration of 2-Substituted 4, 6-Dihydroxypyrimidines.
Nucleophilic Cleavage of the Nitration Products, Russ. J. Org. 2001, 37(5), 729-733.
14.
(a) Bellamy, A. J.; Latypov, N. V.; Goede, P. Nitration of the 6-Methyl-1, 3, 5-
Triazine Derivatives, 6-Methyl-1, 3, 5-Triazine-2, 4 (1H, 3H)-dione and 2, 4-Dimethoxy-
6-methyl-1, 3, 5-triazine, J. Chem. Res. 2003, 2003(9), 529-530; (b) Bellamy, A.;
Latypov, N.; Goede, P. In New Trends in Research of Energetic Materials, 7th
International Seminar. Pardubice, Czech Republic. 2006, 641-651.
15.
Kushtaev, A.; D’yakonov, A.; Yudin, N.; Zbarskii, V. Nitration Kinetics of 6-
Hydroxy-2-methylpyrimidin-4 (3H)-one and 2-Methoxy-2-methylimidazolidine-4, 5-
dione, Russ. J. Appl. Chem. 2009, 82(10), 1785-1791.
16.
Levenspiel, O. Chemical Reaction Engineering, Ind Eng Chem Res. 1999, 38(11),
4140-4143.
20
ACS Paragon Plus Environment

Page 21 of 22
Organic Process Research & Development
1
2
3
4
17.
Eccleston, J. F.; Hutchinson, J. P.; White, H. D. Stopped-Flow Techniques,
5
6
7
Protein Ligand Interactions: Structure and Spectroscopy (Harding, SE, and Chowdry, BZ,
Eds.), Oxford University Press:United Kingdom, 2001, 201-237.
8
9
18.
Business Media: Berlin, 2007.
19. (a) Reid, W. T. Riccati Differential Equations, Academic Press, Elsevier:United
Upadhyay, S. K. Chemical Kinetics And Reaction Dynamics, Springer Science &
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
States, 1972; (b) Odibat, Z.; Momani, S. Modified Homotopy Perturbation Method:
Application To Quadratic Riccati Differential Equation of Fractional Order, Chaos,
Soliton Fract. 2008, 36(1), 167-174.
20.
Aris, R. Elementary Chemical Reactor Analysis, Butterworths series in chemical
engineering:Butterworth-Heinemann,2013.
21
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 22
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
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table of Contents graphic
ACS Paragon Plus Environment