Aromatic nitration using nitroguanidine and EGDN

Article abstract of DOI:10.1016/j.tetlet.2008.04.153

Acid catalyzed nitration has been examined using a variety of novel nitration agents: guanidine nitrate (GN) and nitroguanidine (NQ) as well as the simple nitrate ester, ethylene glycol dinitrate (EGDN). Reactions with either activated or deactivated aromatic substrates proceed rapidly and in high yield. Regioselectivity was similar for all nitrating agents examined. The synthetic advantages of liquid EGDN include high solubility in organic solvents, strong nitration activity and ease of preparation.

Full text of DOI:10.1016/j.tetlet.2008.04.153

Tetrahedron Letters 49 (2008) 4449–4451
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Tetrahedron Letters
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Aromatic nitration using nitroguanidine and EGDN
a
a
a
b
Jimmie C. Oxley a, , James L. Smith , Jesse S. Moran , Jonathan N. Canino , Joseph Almog
*
a University of Rhode Island, 51 Lower College Road, Kingston, RI 02881, USA
b Casali Institute of Applied Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Acid catalyzed nitration has been examined using a variety of novel nitration agents: guanidine nitrate
(GN) and nitroguanidine (NQ) as well as the simple nitrate ester, ethylene glycol dinitrate (EGDN).
Reactions with either activated or deactivated aromatic substrates proceed rapidly and in high yield.
Regioselectivity was similar for all nitrating agents examined. The synthetic advantages of liquid EGDN
include high solubility in organic solvents, strong nitration activity and ease of preparation.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 April 2008
Revised 24 April 2008
Accepted 28 April 2008
Available online 1 May 2008
Keywords:
Aromatic nitration
EGDN
Mixed acid
Regioselectivity
1. Introduction
2. Results
Mixed acid nitration is an inexpensive and universal nitration
technique that proceeds rapidly and in excellent yield.1 The actual
nitrating agent is the NOþ2 ion afforded by the ionization of nitric
acid or nitrate salts and nitro compounds in concentrated mineral
acid. The degree of nitration can be controlled by adequately rely-
ing on the strong deactivating nature of the nitro group. Major
drawbacks, however, are harsh conditions and a lack of regioselec-
tivity. Recent reports have utilized exotic nitrates and solvent con-
ditions in attempts to yield a selective transformation.2–6 Research
has considered the nitration mechanism in terms of the intimate
ion-pair and the sigma complex and in terms of an electrophilic
versus charge transfer mechanism.7,8 Such studies are important
in aiding the design of nitrating agents, which show marked
regioselectivity.
One of us (JA) recently reported the regioselective nitration of
several aromatic compounds with urea nitrate and nitrourea.9
Herein, we probe the generality of that work using guanidine
nitrate (GN) and nitroguanidine (NQ) as well as the simple nitrate
ester, ethylene glycol dinitrate (EGDN).
Guanidinium nitrate has been recently reported as the nitration
agent in organic syntheses under acidic conditions.10 The report
claims high preference to the para isomer, however, toluene is
mono-nitrated to give a 64:18 ortho:para ratio and the nitration
of aniline yields a significant portion of m-nitroaniline alongside
the para-nitro isomer.
At room temperature, in concentrated acid, the nitration reac-
tions proceed in excellent yield over short reaction times (Table
1). All the reagents—guanidinium nitrate (GN), nitroguanidine
(NQ), urea nitrate (UN), nitrourea (NU), ammonium nitrate (AN),
nitric acid, and ethylene glycol dinitrate (EGDN)—nitrated the
arene rings in good yield (ꢀ90%) if sulfuric acid were present.
The use of 1, 2 or 4 equiv of nitrating agent had no effect on the
overall yield, and only slight differences were observed in the iso-
meric ratio of products.
Deactivated aromatic substrates—benzonitrile, benzoic acids,
and nitrobenzene—could be nitrated only once under these
conditions, while toluene produced dinitrotoluenes with all the
reagents. The relative strengths of the nitrating reagents were
similar for UN, NU, GN, and NQ. EDGN and AN appeared to be
stronger nitration agents, producing appreciable amounts of
2,4,6-trinitrotoluene (TNT, Scheme 1) from 2,6-dinitrotoluene
and, in the case of AN, producing 3,5-dinitro-o-toluic acid from
o-toluic acid (Table 2).
While differences in selectivity were observed for different
substrates (Table 2), we did not observe meaningful differences
in regioselectivity among the nitrating reagents, which alludes to
a common mechanism for all of them, namely, attack by nitronium
ðNOþ2 Þ. Indeed, all the reagents (GN, NQ, UN, NU, AN, nitric acid,
and EGDN) nitrated the aromatic substrates only in the presence
of sulfuric acid. Attempts to carry out the reaction by suspending
the reagents in the liquid substrate did not proceed at room tem-
perature or with extended heating. No nitration was affected in
acetic anhydride or acetic acid (80 °C) solvents. However, addition
of a catalytic amount of sulfuric acid to a suspension of nitrating
* Corresponding author. Tel./fax: +1 401 874 2103.
E-mail address: joxley@chm.uri.edu (J. C. Oxley).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.153

4450
J. C. Oxley et al. / Tetrahedron Letters 49 (2008) 4449–4451
Table 1
Nitration reaction yields for various nitrating agents and mixed acids
Arene starting material
Yield by nitrating agent, %
UN
EGDN
1a
GN
NQ
NU
AN
2
HNO3
2
(Nitrate equiv)
2
1
2
1
2
1
2
1
Nitrobenzene
Benzonitrile
93
94
78
79
84
93
90
88
94
89
83
97
91
75
97
85
90
73
89
98
84
83
81
93
76
47
84
82
94
85
80
88
94
81
82
94
Benzoic acid
m-Toluic acid
4(p)-NO2 toluene
2(o)-NO2 toluene
o-Toluic acid
Tolueneb
99
94
99
93
96
89
97
99
91
78
87
90
77
95
93
90
78
98
All yields represent direct extraction and workup to give solid products.
a
EGDN can deliver 2 equiv nitrate per mole.
1 equiv toluene results liquid products (unrecovered), percent composition is reported in Table 2.
b
shown that a mixture of nitrotoluene isomers are produce when
toluene is used but only 1,3-dinitrobenzene appears as the nitra-
tion product of nitrobenzene. meta-Xylene, when heated to reflux
in the presence of UN, gave a mixture of nitro-m-xylenes.
O2N
NO2
O2N
NO2
O2NO
ONO2
H2SO4
0-25 o
HO
OH
C
NO2
Scheme 1. Nitration of 2,6-dinitrotoluene to TNT with EGDN.
3. Discussion
The similarity in regioselectivity among the reactants reported
herein is likely a result of the use of sulfuric acid catalyst. We
assume the mechanism in all observed reactions proceeds via ‘free’
nitronium ion. It is reported that the action of sulfuric acid on GN
converts it into NQ and then further dissociation of NQ into the
nitronium ion.10 This same reaction yields NU from the dehydra-
tion of UN.9 The high conversion and rapid completion of the reac-
tions reported in this work indicates rapid formation of NOþ2 .
agent (UN, NU, GN, or NQ) in liquid arenes promoted nitration even
at room temperature. (The nitration of carbazoles has been
reported using acetic acid and urea nitrate but heating (70 °C) or
a catalytic amount of sulfuric acid was often required.11
)
We have previously reported the thermal decomposition of UN
and GN, sealed in the presence of substituted arenes (toluene,
nitrobenzene), yielded nitration products.12 Careful studies have
Table 2
Nitration of various arenes with several nitrating agents
Substrate
Products
EGDN
1:1
Guanidine nitrate
Nitroguanidine
Urea nitrate
Nitrourea
AN
2:1
HNO3
2:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
Nitrobenzene
Benzonitrile
1,3-Dinitrobenzene
1,2-Dinitrobenzene
1,4-Dinitrobenzene
3-Nitrobenzamidea
3-Nitrobenzonitrile
2-Nitrobenzonitrile
4-Nitrobenzonitrile
2-Nitrobenzamidea
3-Nitrobenzoic acid
3-Me-6-Nitrobenzoic acid
3-Me-2-Nitrobenzoic acid
3-Me-4-Nitrobenzoic acid
Me-2,6-Dinitrobenzoic acid
2,4-Dinitrotoluene
TNT
92
8
91
7
2
73
24
91
7
2
91
<1
8
74
24
90
8
2
96
1
1
79
19
90
10
55
21
89
9
2
91
7
2
100
91
79
15
92
8
91
9
100
63
33
96
2
7
4
6
4
>1
100
48
44
9
2
Benzoic acid
m-Toluic acid
100
54
33
100
100
100
100
100
100
100
45
45
5
5
100
13
p-Nitrotoluene
o-Nitrotoluene
100
100
100
100
100
100
91
9
89
11
2,4-Dinitrotoluene
2,6-Dinitrotoluene
TNT
66
22
12
67
33
68
32
81
19
o-Toluicacid
2-Me-5-Nitrobenzoic acid
2-Me-3-Nitrobenzoic acid
3,5-Dinitro-o-toluic acid
2,6-Dinitrotoluene
2,4-Dinitrotoluene
3,4-Dinitrotoluene
2-Nitro toluene
74
26
69
22
9
13
87
2
100
10
89
1
Toluene
17
75
10
89
1
3
16
7
86
17
82
1
11
86
9
91
19
78
2
6
42
2
38
4
2
3
1
59
41
3-Nitro toluene
4-Nitro toluene
2
TNT
2,4-DNT
2,6-DNT
TNT
TNT
1
10
<1
1
<1
1
1
43
Ratio mol:mol, (EGDN used 1:1 mol, 2 equiv nitrate).
a
Benzamide products from the hydrolysis of nitrile product.

J. C. Oxley et al. / Tetrahedron Letters 49 (2008) 4449–4451
4451
Reviewing the publications of researchers observing selective
nitration, it appears that such success was based on tailoring the
solvent system or substrate versus the nitrating agent. Nitrate salts
of aromatic amines have been converted to their respective para-
nitro compounds under mixed acid conditions. Product mixtures
reported were similar to those produced by conventional methods,
and the selectivity of this ‘intramolecular nitration’ was dictated by
activating groups present on the ring.13 However, changes in the
solvent or acid catalyst did affect regioselectivity. Tsang suggested
the high ortho:para ratio in the nitration of toluene may have
resulted from the lack of a ‘free’ nitronium ion.14 He speculated
that a steric effect between polyphosphoric acid and the methyl
substituent of toluene resulted in an intermediate complex which
blocked the ortho position, leading to high para-selectivity. Olah
used nitropyrazole to nitrate benzene/toluene mixtures. Varying
the acid catalyst, large variations in substrate selectivity (nitrobenz-
ene vs nitrotoluene) but no variations in positional selectivity
(ortho:para ꢀ1.4) were observed. This result was attributed to
the varying ability of the acids to generate the nitrating species,
and the rate and position of the nitration are determined in sepa-
rate steps. Olah argued that the free nitronium ion was not gener-
ated; it would have produced an ortho:para ratio of ꢀ2.15 This
argument may apply to the nitro-organic reagents used in this
study.
sodium bicarbonate solution (50 mL) and distilled water (50 mL).
For the benzoic acid derivatives, the carbonate was replaced with
a second water wash. Immediately an aliquot of the extract was
used for analysis. The solvent was then dried over magnesium
sulfate, filtered, and the solvent evaporated to yield the solid
products. (Similar reactions were prepared with acetic acid, acetic
anhydride, or neat arene as the solvent. These did not promote
nitration. In the final case, catalytic sulfuric acid resulted in
nitration products as realized by GC/MS, but no quantification or
workup was performed.)
Note: The fate of the urea and guanidine portion of the nitro-or-
ganic or nitrate salt is not been thoroughly examined. Attempts to
recover the organic portion were met with some success. After
completing the workup of a nitration performed with urea nitrate,
the aqueous fraction was retained and processed as follows: Much
of the water from the aqueous fraction was evaporated to yield
10 mL of an acidic mixture. The mixture was cooled to 0 °C and
4 mL of nitric acid was added. The reaction mixture was stirred
for 1 h in an ice bath and then poured over 30 g of ice. The reaction
mixture was cooled in the freezer overnight and then filtered to re-
cover the precipitate which was determined to be nitrourea in
ꢀ50% yield.
Note: Several reactions were attempted using 2,3-dimethyl 2,3-
dinitrobutane as the nitrating agent. Nitration was not promoted
by this C–NO2 compound in concentrated H2SO4.
Water content in the reaction mixture has been shown to be an
important factor. Use of calcium sulfate (Drierite) to sequester
water has been claimed to produce low ortho:para ratios in the
nitration of arenes.16 Many of the nitrating reagents employed in
this study could be considered as ‘dry’ acids. Nitrourea, compared
to urea nitrate (or NQ vs GN), has effectively one less mole of water
to contribute to the reaction. Similarly, EGDN can be a water-free
source of nitronium ion.
Products were identified using a 5890 series II gas chromato-
graph with a 5971 mass selective detector (GC/MS) fitted with an
Agilent Technologies HP-5MS column (30 m ꢁ 0.25 mm ꢁ 0.25
micron film). Helium was used as the carrier gas and held at a
constant flow of 1 mL/min. The inlet was split with a 5 mL/min
flow, and the temperature kept at 250 °C. The oven program was
as follows: 50 °C initial ramped 20 °C/min to 150 °C then 5 °C/
min to 220 °C and 20 °C/min to 250 °C with a 4 min hold. A solvent
delay of 3 min was used. The detector was maintained at 300 °C
and measured m/z 30–400. For identification, retention time and
fragmentation pattern matching with known compounds was used
alongside the NIST spectral database.
4. Conclusion
Similar regioselectivity is observed for a variety of nitrating
reagents, both organic and inorganic. We interpret this as evidence
of the action of free nitronium ion under acidic conditions. Indeed,
nitration could not be affected without the presence of sulfuric
acid. EGDN is a liquid with good solubility in organic solvents.
These physical properties may make it synthetically useful, and
its nitration strength is as good, or better, than many other nitrat-
ing species.
References and notes
1. Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration; VCH: New York, 1989.
2. Anuradha, V.; Srinivas, P. V.; Aparna, P.; Rao, J. M. Tetrahedron Lett. 2006, 47,
4933–4935.
3. Yang, X.; Xi, C.; Jiang, Y. Tetrahedron Lett. 2005, 46, 8781–8783.
4. Smith, K.; El-Hiti, G. A. Curr. Org. Chem. 2006, 10, 1603–1625.
5. Smith, K.; Liu, S.; El-Hiti, G. A. Ind. Eng. Chem. Res. 2005, 44, 8611–8615.
6. Carmeli, M.; Rozen, S. J. Org. Chem. 2006, 71, 4585–4589.
7. Queiroz, J. F.; Carneiro, J. W. M.; Sabino, A. A.; Sparrapan, R.; Eberlin, M. N.;
Esteves, P. M. J. Org. Chem. 2006, 71, 6192–6203.
8. Tanaka, M.; Muro, E.; Ando, H.; Xu, Q.; Fujiwara, M.; Souma, Y.; Yamaguchi, Y. J.
Org. Chem. 2000, 65, 2972–2978.
9. Almog, J.; Klein, A.; Sokol, A.; Sasson, Y.; Sonenfeld, D.; Tamiri, T. Tetrahedron
Lett. 2006, 47, 8651–8652.
5. Experimental
Urea nitrate and nitrourea were synthesized by published
methods.17 Guanidine nitrate was purchased commercially and
used to synthesize nitroguandine.18 EGDN synthesis is readily
available in the literature.19,20
10. Ramana, M. M. V.; Malik, S. S.; Parihar, J. A. Tetrahedron Lett. 2004, 45, 8681–
8683.
11. Nagarajan, R.; Muralidharan, D.; Perumal, P. T. Synth. Commun. 2004, 34, 1259–
1264.
*
EGDN has properties similar to nitroglycerine and is extremely
sensitive. Synthesis, concentration, storage, and reactions
should be performed with caution .
*
12. Oxley, J. C.; Smith, J. L.; Naik, S.; Moran, J. S. J. Energ. Mater. 2009, 27.
13. Zhang, P.; Cedilote, M.; Cleary, T. P.; Pierce, M. E. Tetrahedron Lett. 2007, 48,
8659–8664.
14. Tsang, S. M.; Paul, A. P.; DiGiaimo, M. P. J. Am. Chem. Soc. 1964, 29, 3387–3390.
15. Olah, G. A.; Narang, S. C.; Fung, A. P. J. Org. Chem. 1981, 46, 2706–2709.
16. Milligan, B.; Miller, D. G.; AIR Prod. Chem.: United States, 1976.
17. Davis, T. L.; Blanchard, K. C. J. Am. Chem. Soc. 1929, 51, 1790–1801.
18. Davis, T. L.; Ashdown, A. A.; Couch, H. R. J. Am. Chem. Soc. 1925, 47, 1063–1066.
19. Urbanski, T. In Chemistry and Technology of Explosives; Pergamon Press: Oxford,
1965; Vol. 2, pp 142–149.
The aromatic substrate (10 mmol) was dissolved in sulfuric acid
(96%) and cooled to 0 °C in an ice bath. The nitrating agent was
added slowly with rapid stirring. After addition and dissolution
of nitrate, the solutions were allowed to stir in the ice bath for
30 min before being allowed to warm and stir at room temperature
overnight. The solutions, which ranged in color from clear to dark
orange, were poured over ice (100 mL) and then extracted twice
with chloroform (2 ꢁ 50 mL) and the extracts washed with 10%
20. Dr. Jai Prakash Agrawal, D.R.D.H. In Org. Chem. Explosives 2006; p 87–123.