A combined experimental and DFT mechanistic study for the unexpected nitrosolysis of: N -hydroxymethyldialkylamines in fuming nitric acid

Article abstract of DOI:10.1039/c8ra03268h

The reaction of dimorpholinomethane in fuming HNO₃ was investigated. Interestingly, the major product was identified as N-nitrosomorpholine and a key intermediate N-hydroxymethylmorpholine was detected during the reaction by ¹H-NMR tracking which indicates that the reaction proceeds via an unexpected nitrosolysis process. A plausible nitrosolysis mechanism for N-hydroxymethyldialkylamine in fuming nitric acid involving a HNO₃ redox reaction is proposed, which is supported by both experimental results and density functional theory (DFT) calculations. The effects of ammonium nitrate and water on the nitrosolysis were studied using different ammonium salts as additives and varying water content, respectively. Observations show the key role of ammonium ions and a small amount of water in promoting the nitrosolysis reaction. Furthermore, DFT calculations reveal an essential point that ammonia, merged from the decomposition of the ammonium salts, acts as a Lewis base catalyst, and the hydroxymethyl group of the substrate participates in a hydrogen-bonding interaction with the NH₃ and H₂O molecules.

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A combined experimental and DFT mechanistic
study for the unexpected nitrosolysis of N-
hydroxymethyldialkylamines in fuming nitric acid†
Cite this: RSC Adv., 2018, 8, 19310
Yu Zhang, Po Zou, Yingbin Han, Yongliang Geng, Jun Luo * and Baojing Zhou*
The reaction of dimorpholinomethane in fuming HNO
3
was investigated. Interestingly, the major product
was identified as N-nitrosomorpholine and
a key intermediate N-hydroxymethylmorpholine was
1
detected during the reaction by H-NMR tracking which indicates that the reaction proceeds via an
unexpected nitrosolysis process. A plausible nitrosolysis mechanism for N-hydroxymethyldialkylamine in
3
fuming nitric acid involving a HNO redox reaction is proposed, which is supported by both experimental
results and density functional theory (DFT) calculations. The effects of ammonium nitrate and water on
the nitrosolysis were studied using different ammonium salts as additives and varying water content,
respectively. Observations show the key role of ammonium ions and a small amount of water in
promoting the nitrosolysis reaction. Furthermore, DFT calculations reveal an essential point that
ammonia, merged from the decomposition of the ammonium salts, acts as a Lewis base catalyst, and
Received 17th April 2018
Accepted 15th May 2018
DOI: 10.1039/c8ra03268h
the hydroxymethyl group of the substrate participates in a hydrogen-bonding interaction with the NH
3
rsc.li/rsc-advances
and H O molecules.
2
Interestingly, when nitryl chloride, nitrogen pentoxide, nitryl
uoride, nitronium uoroborate and tetranitromethane were
Introduction

N-Nitramines and N-nitrosamines are present in a wide range of used for the N-nitration of secondary or tertiary amines at low
drug molecules, functional organic chemicals and energetic temperatures, nitrosamine products were obtained with low
1
9
materials. For example, some N-nitrosamines have biological yields. Our group made efforts to synthesize HMX by nitrolyzing
activity and can be used in various treatments for illnesses 3,7-dinitro-1,3,5,7-tetraazabicyclo[3.3.1]nonane (DPT) with tradi-
including cancer, cardiovascular diseases, central nervous, and tional nitration systems such as fuming HNO
3
, HNO
3 2 4
–H SO ,
2
ꢀ
diseases related to immunity and physiological disorders. N- HNO
3
–N
2
O
5
, and HNO
3
–Ac
2
O below 0 C, but 1-nitroso-3,5,7-
3
Nitrosamines are valuable intermediates in organic synthesis
trinitro-1,3,5,7-tetraazacyclooctane (MNX) was achieved as the
NO can inevitably improve the
and mesoionic- yield of MNX. Recently, the so called “small-molecule route”
heterocyclic compounds like sydnones. N-Nitrosamines can using urea as the starting material to prepare HMX via DPT has
such as in application for the preparation of biologically main product. Furthermore, NH
4
3
4
8f
important a-disubstituted hydrazines
5
10
also be applied as a nitroso source to prepare aryl C-nitroso been thought to be a promising method for scale-up. Although
compounds in good yield through a Fischer-Hepp rearrange- the development of various techniques has enhanced the yield of
6
ment. Recently, N-nitroso functionality has emerged as HMX by the nitrolysis of DPT, no signicant progress in practical
11
a traceless directing group for the activation of inert C–H bonds potential has been achieved. The main reason is attributed to
7
8e,8f
in aryl rings by associating with transition metals. Further- the ambiguity of the nitrolysis mechanism.
It’s widely
more, some widely used explosives with excellent performances considered that the bridging methylene of the DPT is cleaved to
such as 1,3,5-trinitro-1,3,5-triazacyclohexane (RDX), 1,3,5,7- produce an extremely active intermediate 1-hydroxymethyl-3,5,7-
1
2
tetranitro-1,3,5,7-tetraazacyclooctane (HMX) and 2,4,6,8,10,12- trinitro-1,3,5,7-tetraazacyclooctane. The addition of NH
hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) belong to can hinder esterication (O-acetylation in HNO –Ac O and
) but promote dehydroxymethylation
NO
4
3
3
2
the N-nitramine group, which can be prepared from acetamides N-nitraton in fuming HNO
3
8
8e,8f,11,12
and N-nitrosamines through nitrolysis or oxidation.
to improve the HMX yield.
However, there is no sufficient
or direct experimental evidence to support the above mechanism
because of the rapid reaction characteristics of the nitrolysis
process, and the production of a complex by-product, and a short-
School of Chemical Engineering, Nanjing University of Science and Technology,
Nanjing 210094, China. E-mail: luojun@njust.edu.cn; bzhou@njust.edu.cn
12
lived intermediate.
In this work, we selected a bridging methylene diamine
dimorpholinomethane as a model substance and investigated
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c8ra03268h
1
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ꢀ
in detail its reaction in fuming nitric acid to mimic the nitrol- acid. To verify this, the reaction was performed at 0 C for 10
ysis of DPT. Interestingly, nitrosomopholine was obtained as minutes, then the reaction mixture was poured into ice water,
the main product and the key intermediate N-hydrox- extracted with cold dichloromethane, and washed with ice
1
ymethylmorpholine was detected by H-NMR tracking during water to neutralise it. A yellow oily liquid was obtained by rotary
1
the reaction. Based on experimental observations, a plausible evaporation at room temperature. According to the H-NMR
mechanism for the nitrosolysis of N-hydroxymethyldialkyl- spectrum, three compounds can be identied (Fig. 1a). As
amines in fuming nitric acid is proposed. We further provide shown in Fig. 1b, the chemical shis of the dimorpholino-
14
computational results for the possible reaction mechanism at methane occur at 3.70–3.69, 2.91, 2.50 ppm. Clearly, the
the molecular level using the density functional theory (DFT), mixture mainly consists of dimorpholinomethane. As shown in
which is one of the popular routes to understand the course of Fig. 1c, hydrogen atoms observed at 4.13, 3.74–3.69 and 2.72–
13
14
an organic reaction.
2.67 ppm are assigned to N-hydromethylmorpholine.
Comparing Fig. 1a with 1c, we can distinguish N-hydro-
methylmorpholine from the mixture. However, N-nitro-
morpholine, whose chemical shi is at 3.83 ppm (Fig. 1d), is not
found in the mixture. Moreover, comparing Fig. 1a with 1e, we
found that the chemical shis at 44.31–4.29, 3.91–3.86 and
Results and discussion
0
Similar to DPT, dimorpholinomethane has the N,N -methylene
motif. Therefore, we rst examined the reaction of the dimor-
pholinomethane with fuming nitric acid. To our surprise, N-
nitrosomorpholine was obtained rather than N-nitromorpho-
line when the reaction was carried out at room temperature
3
.68–3.66 ppm in the former spectrum belong to N-nitro-
14a
somorpholine. Thus, N-hydroxymethylmorpholine is formed
during the reaction and nitrosolysis is predominant at room
temperature in classical nitration systems.
(Table 1, entry 1). Prolonging the reaction time increased the
Although N-hydroxymethylmorpholine was observed in the
reaction, it is not clear whether it is an intermediate or a by-
product. To shed some light on this, we prepared a mixture of
N-hydroxymethylmorpholine and dimorpholinomethane as the
substrate for the reaction. As shown in Table 2, N-nitro-
somorpholine is still the major product in fuming nitric acid,
and only 3% of N-nitromorpholine is obtained (entry 1). The
yields of N-nitrosomorpholine and N-nitromorpholine increase
with the elongation of the reaction time (entries 1–3). In
contrast, with an elevation in the reaction temperature, the yield
of N-nitrosomorpholine rst increases and then decreases
yield of N-nitrosomorpholine (entries 2, 3). A small amount of
N-nitromorpholine was isolated aer reacting for 12 hours
(
2
(
entry 3). When the reaction temperature was elevated from
ꢀ
ꢀ
5 C to 40 C, both of them were obtained with higher yields
ꢀ
entry 4). A further increase of the reaction temperature to 70 C
afforded a lower yield of N-nitrosomorpholine but a higher yield
of N-nitromorpholine (entry 5). It is well known that NH NO
4
3
11
plays a key role in the nitrolysis of DPT. Here, similarly, the
yield of N-nitrosomorpholine increased dramatically when
NH NO was used as an additive to the reaction mixture (entry
4 3
6).
4 3
(entries 1, 4, 5). Once again, NH NO signicantly promotes
It is generally accepted that 1-hydroxymethyl-3,5,7-trinitro-
,3,5,7-tetraazacyclooctane is a key intermediate during the
nitrosolysis (entry 6). These observations are similar to those
1
nitrolysis of DPT in fuming nitric acid. Accordingly, we
hypothesized that N-hydroxymethylmorpholine is the interme-
diate in the reaction of dimorpholinomethane in fuming nitric
Table 1 The results for the reaction of dimorpholinomethane in
a
3
fuming HNO
c
Yield /%
Reactant
system
ꢀ
Substrate
Entry
T/ C
t/h
1
2
3
4
5
6
HNO
HNO
HNO
HNO
HNO
HNO
3
3
3
3
3
3
25
25
25
40
70
25
1
4
12
1
1
10
18
25
29
15
31
0
0
5
10
16
0
1
Fig. 1 H-NMR spectrum of: (a) the product from the reaction of
ꢀ
b
dimorpholinomethane in fuming HNO
dimorpholinomethane; (c) the mixture of N-hydromethylmorpholine
3
at 0 C for 10 minutes; (b)
/NH
4
NO
3
1
a
Unless otherwise noted, dimorpholinomethane (5 mmol), fuming and dimorpholinomethane; (d) N-nitromorpholine; (e) N-
b
c
HNO
3
(200 mmol). NH
4
NO
3
(12.5 mmol). Isolated yield.
nitrosomorpholine.
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a
3
Table 2 The results for the reaction of N-hydroxymethyldialkylamines in fuming HNO
Nitrosamine
product
Nitrosamine
yield /%
Nitramine
product
Nitramine
yield /%
b
h
h
Substrate
Entry
1
Reactant system
HNO
HNO
HNO
HNO
HNO
HNO
HNO
HNO
HNO
HNO
HNO
3
3
3
3
3
3
3
3
3
3
3
21
30
35
33
25
51
46
49
47
21
39
3
6
12
9
18
2
3
2
2
0
c
2
d
3
e
4
f
5
g
6
7
8
9
/NH
/(NH
/NH
4
NO
gSO
Cl
3
g
4
)
2
4
4
g
/CH
3
COONH
4
1
1
0
1
g
/NH
4
NO
NO
3
0
1
1
2
3
HNO
HNO
3
19
38
4
4
g
3
/NH
4
3
a
ꢀ
b
Unless otherwise noted, fuming HNO
3
(200 mmol),
T
¼
25
C,
t
¼
1
h.
Substrate (5 mmol), n(N-
1 : 1.25, n(N-
(12.5 mmol); NH Cl (12.5
hydroxymethylmorpholine) : n(dimorpholinomethane)
¼
1 : 1.1, n(N-hydroxymethylpiperidine) : n(dipiperidinemethane)
¼
c
d
e
ꢀ
f
ꢀ
g
hydroxymethyldibutylamine) : n(dibutylamine) ¼ 1 : 1.17. t ¼ 4 h. t ¼ 12 h. T ¼ 40 C. T ¼ 70 C. NH
4
NO
3
4
h
3 4 4 2 4
mmol); CH COONH (12.5 mmol); (NH ) SO (6.25 mmol). Isolated yield.
3
made in the nitrosolysis of dimorpholinomethane. Thus, N- of water into freshly prepared 100% HNO . As shown in Fig. 2,
hydroxymethylmorpholine should be an intermediate in the the yield of N-nitrosomorpholine rst increases and then
reaction, rather than a by-product. The nitrosolysis of the decreases with the increase of water content. The highest yield
mixture of N-hydroxymethylmorpholine and dimorpholino- of 21% was obtained when ca. 5% water was added. Meanwhile,
methane was further carried out in fuming nitric acid/ a small amount of N-nitromopholine was observed in all cases.
ammonium salts containing (NH
4
)
2
SO
4
, NH
4
Cl, and CH
3
-
These results suggest that ca. 5% water is optimal for the
COONH . Similar to NH NO , these ammonium salts can also nitrosolysis of the mixture of N-hydroxymethylmorpholine and
4
4
3
improve the yield of N-nitrosomorpholine (entries 7–9).
We further examined the nitrosolysis of the mixture of N-
dimorpholinomethane.
2
Considering the fact that only very little HNO and its
hydroxymethylpiperidine with dipiperidinemethane and that of analogues are present in fuming nitric acid, it is puzzling that
N-hydroxymethyldibutylamine with dibutylamine in the fuming the product is mostly N-nitrosamine in the above reactions. It is
HNO , respectively. As shown in Table 2, the main products are natural to surmise that a redox reaction has occurred. It is
3
15
+
identied to be N-nitrosamines (entries 10, 12). To estimate plausible that N-hydroxymethyldialkylamines react with NO to
the interference of dibutylamine, we calculated its amount in
the mixture according to the proton NMR test. Then an equal
amount of dibutylamine was used as the substrate for a reaction
under common reaction conditions, which was monitored by
gas chromatography. Only less than 4% N-nitrosodibutylamine
(gas chromatography yield) was detected over 2 h. So we
conclude that the N-nitrosodibutylamine is formed predomi-
nantly by the nitrosolysis of N-hydroxymethyldibutylamine. The
achieved yield of N-nitrosopiperidine and N-nitrosodibutyl-
amine in the fuming HNO
respectively, much higher than for the reactions without
NH NO (entries 10–13).
3 4 3
/NH NO system was 39% and 38%
4
3
The inuence of water on the nitrosolysis of the mixture of N-
hydroxymethylmorpholine and dimorpholinomethane was
evaluated by performing the reaction in water-containing nitric
acid, which was prepared by the addition of different amounts
Fig.
2 The effect of water on the nitrolysis of N-
hydroxymethylmorpholine.
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afford the N-nitrosoamines and release formaldehyde, which
reduces nitric acid to nitrous acid. Then nitrous acid can be
viewed as a catalyst. To further verify this viewpoint, three
secondary amines were reacted in the fuming nitric acid with or
without paraformaldehyde (Table 3). It turned out that N-
nitrosamines were obtained in less than 6% yield in the absence
of paraformaldehyde (entries 1, 3, 5). The addition of para-
formaldehyde greatly increases the yield (entries 2, 4, 6). These
results suggest that N-hydroxymethyldialkylamines are formed
as the more active intermediates under the acidic conditions
13
when paraformaldehyde is present.
In the above reaction, some N-nitromorpholine was observed
and its amount increased with the reaction time (Table 2,
entries 1–3). To investigate whether it was formed from the
nitrolysis of N-nitrosomorpholine, we monitored the reaction of
ꢀ
1
N-nitrosomorpholine in fuming nitric acid at 40 C by H-NMR
spectroscopy. As shown in Fig. 3a, no N-nitromorpholine was
observed at the end of the feeding process (Fig. 3a). However, N-
nitromorpholine gradually formed with an increase in the
reaction time as indicated by the chemical shi of 3.83 ppm in
1
Fig. 3 H-NMR spectra of samples taken from the reaction mixture at:
a) the end of the feeding process; (b) 2 hours; (c) 4 hours (d) 6 hours.
(
15
3
molecules. In another reaction model, the NH molecule was
replaced by a H O molecule. Interestingly, we found that the
2
free ammonia, formed from the unfavourable balance with
NH4 in an acidic environment, is a Lewis base catalyst, while
water molecules are essential for the formation of the hydrogen
bond (HB) adduct. A bicyclic ring was inferred from the bond
2
angle of H O molecules. The optimized structures of the reac-
tants, transition states (TSs), and products from the two reac-
tion models in the presence (model a) or absence (model b) of
NH are compared in Fig. 4.
3
For both models, we found that NO is not involved in the
bicyclic ring formed from the HB interactions and it approaches
the N atom in the substrate from the other side. In the TS, the
N–N bond forms, and the C–N bond is breaking, while the H is
transferring from the hydroxyl group to the NH
O molecule (model b), which suggests a synergistic mecha-
nism. The computed relative Gibbs free energy proles for
Fig. 3b and c and its proportion increased with the disap-
pearance of N-nitrosomorpholine. Aer 6 hours, almost all of
the N-nitrosomorpholine had been converted to N-nitro-
morpholine (Fig. 3d). On the other hand, some N-nitroamines
may have been generated by the oxidation of the N-nitrosa-
+
8
mines. To examine this possibility, the reactions of nitro-
somorpholine in 90% HNO , 80% HNO , 70% HNO , 60%
3
3
3
HNO , and 50% HNO were investigated. Almost no product,
3
3
however, was detected even when the reaction temperature
ꢀ
ꢀ
changed from 20 C to 80 C. Thus, we conclude that N-nitro-
morpholine is mainly formed through the nitrolysis of N-
nitrosomorpholine in fuming nitric acid.
+
We further performed a computational study to investigate
the reaction mechanism at the atomic level. Two reaction
models were constructed. The rst reactant model contained
3
(model a) or
H
2
one N-hydroxymethyldialkylamine, one NH3 and three H O
2
models a and b are summarized in Fig. 5. For model a, the
ꢁ
1
predicted Gibbs free energy of activation is 3.3 kcal mol . For
Table
paraformaldehyde
3 The nitrosation of secondary amines is promoted by
ꢁ1
a
model b, the reaction barrier is 13.7 kcal mol , which is
ꢁ
1
1
0.4 kcal mol higher than that of model a. These results
indicate that the NH molecule plays the role of a catalyst.
Therefore, the addition of NH
3
+
4
can signicantly promote the
nitrosolysis of N-hydroxymethyldialkylamines.
n(substrate) :
The gradual changes of the four chemical bonds along the
reaction coordinate are illustrated in Fig. 6. First, the hydroxyl H
is extracted by the N of ammonia, which leaves the negative
charge on the N-hydroxymethyldialkylamine substrate. Then
b
Substrate
Entry
n(CH
2
O)
Product
Yield /%
1
2
0
1 : 1
6
33
+
the electrophilic attack is initiated by NO as indicated by its
decreasing separation from the N atom of the substrate. When
the N–N bond is half formed, the C–N and O–H bonds break,
which leads to the formation of the products, i.e. nitrosamine,
formaldehyde, and ammonium. The highly synchronous vari-
ations further indicate the concerted reaction mechanism for
the nitrolysis of N-hydroxymethylmorpholine.
3
4
0
1 : 1
4
51
5
6
0
1 : 1
3
65
a
(200 mmol) T ¼ 25 ꢀC, t ¼ 1 h.
Substrate (5 mmol), fuming HNO
Isolated yield.
3
Based on our experimental and theoretical results and the
b
8
e,8f,11,12
related reports,
we propose a plausible mechanism for
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Fig. 6 Bond cleavages and formations along the IRC path of the
nitrosolysis of N-hydroxymethylmorpholine.
Fig. 4 Optimized structures for the two reaction models representing
the nitrosolysis of N-hydroxymethylmorpholine. Model a contains an
NH
a H
3
molecule, while in model b, the NH
O molecule. O: red, C: dark grey, H: light grey, N: blue.
3
molecule is replaced by
2
the formation of N-nitrodialkylamines from N-hydrox-
Scheme 1 Possible reaction mechanism for the nitrosolysis of N-
ymethyldialkylamines in fuming nitric acid and an ammonium hydroxymethyldialkylamine.
nitrate system (Scheme 1). First, a small amount of HNO in
emerges
. The substrate
2
+
fuming HNO
3
is converted to NO and some free NH
NO
3
+
attack of NO . Then N-nitrosamine forms along with the
through the equilibrium reaction with NH
4
3
departure of formaldehyde. Subsequently, formaldehyde is
is conjoined to one ammonia and three water molecules by HB
interactions to form the pre-reactive complex in situ. Then, the
16
oxidized by HNO to form HCOOH. Simultaneously, HNO is
3
3
reduced to HNO2 to complete one nitrosolysis cycle. N-Nitr-
amine is afforded from N-nitrosamine by the replacement of the
nitroso group with a nitro group via a nitrolysis process.
NH abstracts the hydrogen from the hydroxyl group to increase
3
the electron density of the tertiary N atom, which facilitates the
Conclusions
We synthesized N-nitrosodialkylamines from N-hydrox-
ymethyldialkylamines in fuming HNO via nitrosolysis. The
3
reaction mechanism at the molecular level was established
based on experimental observations and DFT calculations and
3 2
involves a redox reaction of HNO to afford HNO . The DFT
calculations indicate that the nitrosolysis reaction proceeds very
smoothly with a rigid bicyclic transition state consisting of N-
hydroxymethyldialkylamine, ammonia and water.
Experimental section
General procedure for the nitrosolysis of the mixture of N-
hydroxymethyldialkamines in fuming nitric acid
The mixture of N-hydroxymethyldialkamines (5 mmol) was
Fig.
5 Energy profile for the nitrosolysis of N-hydrox-
ymethylmorpholine in the presence or absence of NH
3
.
added in portions to fuming nitric acid (200 mmol) under
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ꢀ
vigorous stirring at 0 C, and the reaction mixture was then
warmed to a certain temperature. The reaction was quenched by
being poured into ice water (20 mL). The resulting mixture was
extracted with dichoromethane (3 ꢂ 30 mL). The combined
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3
organic layer was washed with saturated NaHCO and dried
with Na
2
SO
4
. Aer ltration, the mixture was concentrated
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under reduced pressure to afford the crude product, and the
desired product was obtained by column chromatography.
The same procedure as described above was used for the
nitrosolysis of dimorpholinomethane.
Conflicts of interest
There are no conicts to declare.
4
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D. D. Li, Y. X. Cao and G. W. Wang, Org. Biomol. Chem.,
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2
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Notes and references
8
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