An efficient process for the synthesis of gem-dinitro compounds under high steric hindrance by nitrosation and oxidation of secondary nitroalkanes

Article abstract of DOI:10.1016/j.tetlet.2018.05.002

A new nitrosation and oxidation process to synthesize gem-dinitro compounds was accomplished by using nitryl chloride as nitrosation reagent and ozone as oxidizing agent. The main features of the present protocol include the compatibility to substances with high steric hindrance, high yields and mild reaction conditions. A plausible mechanism involving the formation of an intermediate of gem-nitrosonitro compound by means of single electron transfer was also proposed.

Full text of DOI:10.1016/j.tetlet.2018.05.002

Accepted Manuscript
An efficient process for the synthesis of gem-dinitro compounds under high
steric hindrance by nitrosation and oxidation of secondary nitroalkanes
Jian Zhang, Tianjiao Hou, Yifei Ling, Lin Zhang, Jun Luo
PII:
S0040-4039(18)30583-5
https://doi.org/10.1016/j.tetlet.2018.05.002
TETL 49949
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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18 March 2018
21 April 2018
2 May 2018
Please cite this article as: Zhang, J., Hou, T., Ling, Y., Zhang, L., Luo, J., An efficient process for the synthesis of
gem-dinitro compounds under high steric hindrance by nitrosation and oxidation of secondary nitroalkanes,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.002
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Tetrahedron Letters
An efficient process for the synthesis of gem-dinitro compounds under high steric
hindrance by nitrosation and oxidation of secondary nitroalkanes
Jian Zhanga, Tianjiao Houa, Yifei Lingb, Lin Zhang a and Jun Luoa
a
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new nitrosation and oxidation process to synthesize gem-dinitro compounds was
accomplished by using nitryl chloride as nitrosation reagent and ozone as oxidizing agent. The
main features of the present protocol include the compatibility to substances with high steric
hindrance, high yields and mild reaction conditions. A plausible mechanism involving the
formation of an intermediate of gem-nitrosonitro compound by means of single electron transfer
was also proposed.
Available online
Keywords:
gem-dinitro compound
nitrosation
2018 Elsevier Ltd. All rights reserved.
oxidation
steric hindrance
nitryl chloride
single electron transfer
Introduction
For centuries, extensive efforts have been devoted to the development of new high energy density materials (HEDMs) that meet
the criteria of both higher energy and better safety properties[1-5]. Due to the positive correlation between detonation velocity,
detonation pressure, specific impulse and density, the demand for higher energy density is gradually increasing[6]. Currently, there
are several known functionalities that can increase the density of energetic compounds, such as nitro, azido, nitroxy, nitramino,
difluoramino, gem-difluoramino and gem-dinitro. It is critical to introduce suitable functionalities with certain number on the
skeletons of target energetic compounds due to the inherent contradiction between detonation performance and stability.
Polynitroaliphtic compouds have not found widespread use as either commericial or military explosives up to now because most
of them, containing internal gem-dinitroaliphatic functionality, have high chemical and thermal stability. But this property is of
great importance nowadays owing to the increasing requirement of energetic compounds with low sensitivity and good heat-
resistance. Besides, gem-dinitro groups can give the energetic compounds higher density and better oxygen balance in comparison
with aromatic C-nitro compounds.
Although a large number of gem-dinitro compouds have been synthesized[7], the methods for efficiently and simply constructing
gem-dinitro functionality are still limited. Generally, there are two approaches to do this work. One is oxidative nitration of
nitroalkanes under basic conditions. For example,
———
 Corresponding author. e-mail: zhangl@njust.edu.cn
 Corresponding author. e-mail: luojun@njust.edu.cn

3
Scheme 1. Processes for the synthesis of gem-dinitro compounds.
Kaplan and co-workers prepared gem-dinitro compounds from sodium nitronates with AgNO3/NaNO2 through a free radical
mechanism (Scheme 1a)[8]. However, this method has the fatal drawback in heavy use of expensive AgNO3 as oxidant.
Subsequently, some efforts had been made to use much cheaper oxidants such as stoichiometric potassium ferricyanide or catalytic
amount of potassium ferricyanide with stoichiometric amount of persulfate anion as co-oxidant (Scheme 1b), but still no obvious
improvement in reaction yield had been achieved[9]. In addition, under electrochemical conditions, sodium nitronates can react
directly with sodium nitrite to afford gem-nitro compounds (Scheme 1c)[10]. Lister and co-workers improved this process and their
following project was to investigate pilot-plant scale reaction[11]. The other approach for constructing gem-dinitro functionality is
tandem nitrosation-oxidation of oximes by Scholl method[12] via the intermediate of pseudonitrole[13] (Scheme 1d).
As potential candidates of HEMDs, polynitroadamantanes have attracted widespread attention[14]. In 1988, the oxidative nitration
of nitroadamantanes with AgNO3/NaNO2 was studied by Archibald and co-workers[15]. For example, 2-nitroadamantane was
converted to 2,2-dinitroadamantane in 89% yield while both 2,4-dinitroadamantane and 2,6-dinitroadamantane did not give gem-
dinitro derivatives by this methods. Meanwhile, direct nitration of 2,4-adamantanedionedioxime resulted in the Nef reaction product
2,4-adamantanedione and the intramolecular ring-closure byproduct 2,4-dinitro-2,4-dinitrosoadamantane[16]
.
For 2,6-
dinitroadamantane, its gem-dinitro product 2,2,6,6-tetranitroadamantane can be achieved by reaction in NaOH/C(NO2)4 system.
However, this protocol failed for the case of 2,4-dinitroadamantane. The reason might be assigned to the high steric hindrance. In
fact, there are no reports on the synthesis of polynitroadamantanes that contain seven or more nitro groups.
In order to synthesize polynitroadamantanes containing more gem-dinitro groups, more efficient processes for introducting gem-
dinitro functionality to carbons with high steric hindrance are still required. In this paper, an efficient process for the conversion of
nitroalkanes to gem-dinitro compounds via nitrosation with nitryl chloride and oxidation with ozone is reported.
Results and discussion
Eaton and co-workers[17] tried to synthesize octanitrocubane by direct electrophilic nitration of various alkali salts of
heptanitrocubane with N2O4, NO2Cl, NO2BF4, NO2PF6 and some nitrate esters but failed at all. Finally, they accomplished this
target through the tandem reactions of nitrosation and oxidation. Some similar reaction process that electrophilic reagents reacted
directly with metal salts were also reported[18]. Refer to this method, 2,2,4-trinitoadamantane (1) was use as the model substrate to
optimize the reaction conditions and the results was listed in Table 1.
Firstly, the oxidative nitration with AgNO3/NaNO2 was attempted, but no target product 2,2,4,4-tetranitroadamantane (1a) was
obtained (Table 1, Entry 1). When a large excess of N2O4 (15 equivalents) was used and the reaction was carried out at -30℃, the
green nitrosation intermediate was observed. But unfortunately, the effort to separate it out of the reation mixture failed. After
oxidizing with ozone, the target product 1a was isolated in an overall yield of 35% (Table 1, Entry 2). It was once thought to be an
electrophilic reaction between nitrosonium ion (NO+) and carbon anion in the first step. But when NOCl[19] was used as nitrosating
reagent, the target product 1a was obtained in much lower yield of 16% (Table 1, Entry 3). As a result, the formation of
pseudonitrole might not be the classical electrophilic nitrosation process. NO2BF4 and NO2Cl were used as nitrating agents long

4
before[20]. To our surprise, when highly active nitrating reagents NO2BF4 or NO2Cl were applied, the green nitrosation intermediate
still formed according to the experimental phenomena. With the inletting of ozone, the green mixture gradually changed to colorless
and afforded 1a. For the case of NO2BF4, the yied was still very low and comparable to that of NOCl (Table 1, Entry 4). To our
delight, the yield was dramatically elevated to 66% when NO2Cl was applied (Table 1, Entry 5). Increasing the dosage of NO2Cl
from 15 equivalents to 20 equivalents could further improve the yield to 77% (Table 1, Entry 6). More NO2Cl (25 equiv.) resulted in
no obvious change of yield (Table 1, Entry 7). Decreasing the reaction temperature could improve the yield in a certain extent
(Table 1, Entries 8 and 9). The yield decreased obviously when the reaction time was shortened to 1 hour (Table 1, Entry 10).
Longer time didn’t improve the yield (Table1, Entries 11 and 12). From Table 1, the optimum reaction conditions involve the
nitrosation of 1 with NO2Cl (20 equiv.) in CH2Cl2 at -70℃ for 2 h and the oxidation with ozone (Entry 9).
Table 1. Preparation of 2,2,4,4-tetranitroadamantane through
nitrosation and oxidation of 2,2,4-trinitroadamantane.[a]
Nitrating
reagent
Usage
[equiv.]
Temperature
Time
[h]
Yield[c]
[%]
Entry
[℃]
[b]
1
2
NaNO2
5
20
1
2
2
2
2
2
2
2
2
1
3
4
--
N2O4
NOCl
15
15
15
15
20
25
20
20
20
20
20
-30
-30
-30
-30
-30
-30
-50
-70
-70
-70
-70
35
16
20
66
76
77
83
87
61
85
85
3
4
NO2BF4
NO2Cl
NO2Cl
NO2Cl
NO2Cl
NO2Cl
NO2Cl
NO2Cl
NO2Cl
5
6
7
8
9
10
11
12
[a] Reaction conditions: (1) compound 1 (1 mmol), CH3ONa (1.1 mmol),
CH3OH (5 mL), RT, 4 h; (2) compound 1’, nitrating or nitrosating reagents,
CH2Cl2 (100 mL); then ozone was bubbled into the system until the system
became colourless. [b] AgNO3 (3 mmol, 3 equiv.), ethanol (10 mL), water
(10 mL). [c] Isolated yield.
With the optimum conditions in hand, several high sterically hindered secondary nitroalkanes, mainly polynitroadamantanes,
were examined. It can be seen from Table 2 that 2-nitroadamantane (2) and 2,6-dinitroadamantane (3) were smoothly converted to
their gem-dinitro products in excellent yields (Table 2, Entries 1 and 2). To our deligt, a very high
Table 2. Substrate scope for the nitrosation and oxidation tandem
process leading to the gem-dinitro compounds[a].
Entry
Substrate
Product
Yield[b]
1
88

5
2
3
82
85
4
80
40
5
6
45
_
ND[c]
7
8
76
83
79
70
9
10
[a] Reaction conditions: (1) nitro compound (1 mmol), CH3ONa (1.1
mmol), CH3OH (5 mL), RT for 4 h; (2) sodium nitronate (1 mmol), NO2Cl
(20 mmol, 20 equiv.), CH2Cl2 (100 mL), -70℃ for 2 h, then ozone was
bubbled into the system until the system was colourless. [b] Isolated yield.
[c] not detected.
sterically hindered substrate 2,2,4,6,6-pentanitroadamantane (4), was very compatible to this method and furnished gem-dinitro
product 2,2,4,4,6,6-hexanitroadamantane (4a) in 85% yield with a little byproduct of Nef reaction, 2,2,6,6-tetranitro-4-
adamantanone (Table 2, Entry 3). Similarily, another high sterically hindered substrate 2,4,4,6-tetranitroadamantane (5) also gave
the target product 4a in 80% yield (Table 2, Entry 4). Compound 4a was firstly synthesised by Dave and co-workers[21] from
dimethyl malonate and paraformaldehyde via a 10-step route in 0.24% overall yield. And in 2014, our group reported an improved
strategy by using N2O5 as nitrating reagent[14c]. As a result, the yield of direct nitration of 2,6-bis(hydroxyimino)-4,4-
dinitroadamantane was improved from 21% to 47%, which was still low relatively. By contrast, the new approach was more
efficient.

6
However, when the nitronate anions were on 2,4-positions, the reaction produced no traget products without expection. For
example, 2,4-dinitroadamantane (6) resulted in an intramocular ring-closure product 2,4-dinitro-2,4-dinitrosoadamantane (6b)[15]
(Scheme 2) and 2,4-adamantanedione (6c) (Table 2, Entry 5). The structure of 6b was confirmed by X-ray single crystal diffraction
and NMR test. The crystal density of 6b was determined to be 1.64 g cm-3, which was a little lower than 2,2,4,4-
tetranitroadamantane (1.65 g cm-3). The thermal stability of 6b was determined by differential scanning calorimetry (DSC) and
thermogravimetry (TG). The results show that the onset decomposition temperature of 6b is 166.5℃ while that of 2,2,4,4-
tetranitroadamantane is 223.8℃. In addition, the formation of 6b also supports the fact that the reaction may proceed through
nitrosation[22]. For 2,4,6-trinitroadamantane (7), only some unidentified byproducts were obtained (Table 2, Entry 6). In addition, a
number of arylnitroalkanes such as p-(1-nitroethyl)chlorobenzene, p-(1-nitroethyl)anisole, 1-nitroethylbenzene and 1-nitro-2,2,2-
trifluoroethylbenzene also proceeded smoothly and afforded the target gem-dnitro products with high yields of 76%, 83%, 79%,
70% respectively (Table 2, Entries 7-10).
Scheme 2. Formation of the intramolecular ring-closure product 6b.
+
As mentioned above, the reaction might not be proceed through the classical electrophilic reaction between nitronium (NO2 ) or
nitrosonium ion (NO+) and carbon anion. We assumed that the reaction mechanism might involve a single electron transfer process,
+
based on the fact that nitronium (NO2 ) and nitrosonium ion (NO+) have the oxidizing ability[23]. To testify this hypothesis, we
added 2 equivalents of TEMPO, a typical free radical trapping agent, into the reaction mixture and no corresponding gem-dinitro
product could be gotten (Scheme 3a). Decreasing the usage of NO2Cl from 20 equivalents to 1 equivalent reduced the yield to be
less than 20%, indicating an additional consumption of NO2Cl except reacting with sodium nitronates (Scheme 3b). Similarly, when
TEMPO (2 equiv.) was added to the reaction mixture with NOCl as nitrosation reagent, no product was afforded either (Scheme 3c).
Scheme 3. Experiments for mechanistic understanding.
Based on the above results, a plausible mechanism for this protocol was postulated (Scheme 4) using 2-nitroadamantane as
model substrate. First of all, a single electron transfer reaction happens between the carbon anion and NO2+ to afford nitroxyl radical
-
and carbon radical. The nitroxyl radical can form dinitrogen tetroxide (N2O4) which can provide NO+ and nitrate (NO3 ) by

7
-
heterolysis. In addition, N2O4 can also be provided from the reaction between NO3 and NO2+ with the release of oxygen. The gem-
nitrosonitro intermediate comes from the radical coupling between carbon radical and NO free radical arrising from the SET
reaction between NO+ and nitroxyl radical. At last, the gem-nitrosonitro product is oxidized to the gem-dinitro derivative with ozone.
Scheme 4. Proposed reaction mechanism.
Conclusions
In conclusion, we reported an efficient method to synthesize gem-dinitro compounds from secondary nitroalkanes with nitryl
chloride as nitrosating reagent and ozone as oxidizing agent. The nitrosation reaction involves a single electron transfer process.
This method is especially suitable for introducing nitro functionality into the secondary nitroalkanes with high steric hindrance.
Acknowledgments
This work was sponsored by Qing Lan Project of Jiangsu Province, P. R. China. The authors are grateful to Dr. Yue Zhao from
Nanjing University for the single-crystal structure analysis.
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Highlights:
 High compatibility to secondary nitroalkanes with steric hindrance
 Presence of single electron transfer in nitrosation of nitronates with nitryl chloride
 Mild reaction conditions comparing to Scholl’s oxidative gem-dinitration of oxime
 Free of noble metal comparing to Shechter‐ Kaplan oxidative nitration

10
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An efficient process for the synthesis of gem-
dinitro compounds under high steric
hindrance by nitrosation and oxidation of
secondary nitroalkanes
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Jian Zhang a, Tianjiao Hou a, Yifei Ling b, Lin Zhang a*, Jun Luo a*