The specific reactivity of 3,4,5-trinitro-1H-pyrazole

Article abstract of DOI:10.1016/j.mencom.2010.09.003

Nitration of 3,5-dinitropyrazole with HNO3-H2SO4 mixture gives 3,4,5-trinitro-1H-pyrazole, which in reaction with ammonia, amines or thiols under mild conditions undergoes regioselective nucleophilic substitution of the 4-positioned nitro group.

Full text of DOI:10.1016/j.mencom.2010.09.003

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 253–254
The specific reactivity of 3,4,5-trinitro-1H-pyrazole
Igor L. Dalinger,* Irina A. Vatsadze, Tatyana K. Shkineva,
Galina P. Popova and Svyatoslav A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: dalinger@ioc.ac.ru
DOI: 10.1016/j.mencom.2010.09.003
Nitration of 3,5-dinitropyrazole with HNO3–H2SO4 mixture gives 3,4,5-trinitro-1H-pyrazole, which in reaction with ammonia,
amines or thiols under mild conditions undergoes regioselective nucleophilic substitution of the 4-positioned nitro group.
Previously,1 we have reported on the synthesis of N-unsub-
stituted all-carbon nitrated pyrazole (3,4,5-trinitro-1H-pyrazole,
1) by the oxidation of 5-amino-3,4-dinitropyrazole with highly
concentrated hydrogen peroxide in concentrated sulfuric acid.
Here we describe an alternative approach to compound 1 by
nitration of 3,5-dinitropyrazole 2 with HNO3–H2SO4 mixture
(Scheme 1). In contrast to our present results, Herve et al.2
report that HNO3–H2SO4 mixture is not sufficient for the nitra-
tion of the 3,5-dinitropyrazole 2 and compound 1 is formed
only upon addition of excess of 60% oleum to the standard
nitration mixture.
with strong bases (NH3, KOAc, 3a,b) but also with weak bases
like N-amino-1,2,4-triazole (3c) (pKBH+ = 3.233).
N-Unsubstituted 3,4,5-trinitropyrazole 1 is prone to unusually
react with nucleophiles. It readily reacts with excess of ammonia
or aliphatic amines under very mild conditions (in water at room
temperature) as well as with thiols in the presence of inorganic
bases, affording compounds 4‡ and 5,§ respectively (Scheme 2). The
latter are the products of 2-positioned nitro group substitution.
Trinitropyrazole 1 is easily hydrolyzed by NaHCO3 solution,
with the corresponding hydrolysis product being isolated as the
disodium salt 6¶ (Scheme 2).
Trinitropyrazole 1 is a strong NH-acid (pKa = 0.05) well
soluble both in water and in a wide range of organic solvents
including diethyl ether, ethyl acetate, dioxane, THF, alcohols,
acetonitrile, DMF and DMSO. Being such a strong acid,
pyrazole 1 forms stable salts of type 3 (see Scheme 1)† not only
It should be of note that formation of products 4–6 is the
first example of the regioselective nucleophilic substitution of
the 4-positioned nitro group in the pyrazole ring. Previously,
only the substitution of a nitro group at 3- or 5-position in
3(5),4-dinitropyrazoles was documented.4 Obviously, the first
‡
Synthesis of 3,5-dinitro-4-NR'R"-1H-pyrazoles 4a–h (general proce-
NO2
dure). To the solution of trinitropyrazole 1 (0.5 g, 2.5 mmol) in water
(5 ml), the appropriate amine (10 equiv. in case of 4a,b and 3 equiv. in
case of 4c–h) was added and the reaction mixture was left for 10 h at
ambient temperature. The precipitate was filtered off, washed with cold
MeOH, suspended in 3 ml of water and acidified with 20% H2SO4 to
pH 1. The resulting precipitate was filtered off, dried and crystallized from
EtOH–H2O (1:1).
O2N
NO2
O2N
NO2
i
N
NH
NO2
N NH
1
3a Cat+ = NH4
3b Cat+ = K+
3c Cat+ =
O2N
NO2
Cat+
ii
4a: yield 80%, mp 166–168 °C. 13C NMR, d: 128.96 (C4), 138.84 (C3,
C5). 14N NMR (acetone-d6) d: –25.15 (n1/2 80 Hz, NO2). IR (KBr, n/cm–1):
3460, 3320, 3190, 1650, 1525, 1350. UV [l/nm (e)]: 260 (12000), 400
(9600) in H2O; 306 (16200), 400 (8400) in aq. NaOH; 222 (12400) in
aq. H2SO4. pKa = 3.42, pKBH+ = –5.43. MS (ESI), m/z: 172.0117 (calc.
for C3H2N5O4–: 172.0112).
N
N
N
N
H3N
N
3a–c
Scheme 1 Reagents and conditions: i, HNO3 (15 equiv.)–H2SO4 (30 equiv.),
90–100 °C, 10 h; ii, MeOH, room temperature, 2 h, base (1 equiv.): a, NH3,
b, KOAc, or c, N-amino-1,2,4-triazole.
1
4b: yield 87%, mp 170–171 °C. H NMR, d: 3.00 (s, 3H). 13C NMR,
The structures of all compounds were established by 1H, 13C, 14(15)N NMR
d: 33.31 (Me), 129.83 (C4), 139.39 (C3, C5). MS (ESI), m/z: 186.0272
†
as well as special correlation NMR techniques such as HMBC, HSQC and
NOESY in DMSO-d6 on a Bruker AC-300 or Bruker DRX-500 spectro-
meter and confirmed by IR-spectroscopy, mass-spectrometry on a KRATOS
MS-30 or MicrOTOFII instrument, and elemental composition data. All
the compounds contain the bands 1325, 1520 cm–1 (NO2) in their IR
spectra, and the appropriate [M]+ in their mass spectra.
3,4,5-Trinitro-1H-pyrazole 1. A solution of 2 (18.6 g, 0.12 mol) in a
mixture of H2SO4 (d = 1.824, 186 ml) and HNO3 (d = 1.51, 75 ml) was
kept at 90–100 °C for 10 h. The resulting mixture was poured into ice-
water (1 dm3), and extracted with ethyl acetate (2×300 ml). The organic
layer was separated, washed with water and dried with MgSO4. The solvent
was then removed, and the residue was crystallized from toluene. Yield,
20.7 g (87%), mp 186 °C (lit.,1 mp 182–184 °C, lit.,2 mp 187.8 °C).
3a: yield 89%, mp 195–198 °C. 13C NMR, d: 122.06 (C4), 146.90 (C3, C5).
3b: yield 95%, mp 199–201 °C. 13C NMR, d: 122.03 (C4), 147.24 (C3, C5).
3c: yield 90%, mp 165 °C. 13C NMR, d: 122.06 (C4), 143.97, 146.91
(C3, C5).
(calc. for C4H4N5O4–: 186.0269).
4c: yield 80%, mp 170–172 °C. H NMR, d: 1.92 (m, 4H), 3.36 (m,
4H). 13C NMR, d: 25.44, 51.92, 125.17 (C4), 141.39 (C3, C5).
4d: yield 74%, Tdecomp. 238 °C. H NMR, d: 3.22 (m, 4H), 3.75 (m,
4H). 13C NMR, d: 50.79, 66.43, 126.22 (C4), 143.50 (C3, C5).
4e: yield 87%, mp 188–190 °C. H NMR, d: 1.65 (m, 8H), 3.24 (m,
4H). 13C NMR, d: 27.60, 29.00, 53.74, 128.14 (C4), 144.15 (C3, C5).
4f: yield 89%, mp 166–168 °C. H NMR, d: 1.61 (m, 6H), 3.12 (m,
4H). 13C NMR, d: 22.68, 25.94, 51.90, 127.60 (C4), 143.06 (C3, C5).
4g: yield 74%, mp 138–139 °C. H NMR, d: 0.93 (d, 3H), 1.30 (m,
1
1
1
1
1
2H), 1.55 (m, 1H), 1.64 (m, 2H), 3.08 (m, 2H), 3.21 (m, 2H). 13C NMR,
d: 21.14, 28.02, 30.22, 34.02, 43.29, 51.25, 127.51 (C4), 146.86 (C3, C5).
4h: yield 84%, Tdecomp. 247 °C. 1H NMR, d: 2.81 (s, 3H), 3.15 (m,
2H), 3.42 (m, 4H), 3.58 (m, 2H). 13C NMR, d: 40.33, 47.35, 52.85,
125.08 (C4), 144.99 (C3, C5).
For the synthesis of compound 4a from carbamate 9, see Online
Supplementary Materials.
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 253–254
The experimental data demonstrate that electrophilicity of
trinitropyrazole 1 is so great that its reactions with nucleophiles
occur under extremely mild conditions.
ONa
O2N
NO2
NNa
The mentioned recent paper2 reports that ‘drastic conditions
are required to provoke 4-NO2 displacement’ which is in
contradiction with our present results. Our colleagues would
attribute such a ‘poor’ reactivity of 4-NO2 to the experimentally
(X-ray) discovered non-coplanarity of this nitro group with the
rest of the system. However, such a statement seems unlikely as
it is well known that non-coplanarity of aromatic nitro group is
usually the true reason for its nucleofugacity, since the forma-
tion of ipso-σ-complex between the nucleophile and the nitro-
(hetero)arene, which is the limiting stage in SNAr reactions,
proceeds at higher rates with such substrates.5
N
6, 28%
NR' R''
NO2
SR
iii
i
ii
O2N
O2N
NO2
1
N
NH
N NH
4a R' = R'' = H
4b R' = H, R'' = Me
4c R' + R'' = (CH2)4
5a R = Et
5b R = Ph
5c R = 4-BrC6H4
5d R = 4-ClC6H4
5e R = 4-ClC6H4CH2
5f R = CH2COOH
4d R' + R'' = (CH2)2O(CH2)2
4e R' + R'' = (CH2)6
The extended explanations on the unusual reactivity of tri-
nitropyrazole 1 based on the structural and theoretical methods
will be published soon.
4f R' + R'' = (CH2)5
4g R' + R'' = (CH2)2C(Me)(CH2)2
4h R' + R'' = (CH2)2N(Me)(CH2)2
Due to the high rate of NH proton exchange in the solutions
of products 3, 4 and 5, their 13C NMR spectra contain only two
carbon signals assigned to C4 and C3,5 atoms of the pyrazole
ring. Additional proofs of the structures were found during NMR
study of compound 8 which was synthesized by N-methylation of
compound 4b. The application of HMBC spectroscopy allows one
Scheme 2 Reagents and conditions: i, HNR'R'' (3–10 equiv.) in H2O,
room temperature, 10 h, then 20% H2SO4; ii, RSH (1.2 equiv.)/NaOH
(2 equiv.) in H2O, room temperature, 3 h, then 20% H2SO4; iii, NaHCO3
(2.5 equiv.) in H2O, 80–90 °C, 9 h.
1
to observe the long distance H–13C coupling constant between
step in all these reactions is the formation of the corresponding
pyrazolate-anion, the substitution in which is the second step
leading to the final products. It is worth noting that nucleo-
philic substitution within the anionic (pyrazolate) species could
not be predictable a priori.
At the same time, in spite of its intrinsic low basicity,
trinitropyrazole 1 could be N-methylated with dimethyl sulfate
under very mild conditions. The reaction proceeds smoothly in
water at ~20 °C in the presence of NaHCO3 giving rise to
another all-carbon nitrated 1-methyl-3,4,5-trinitro-1H-pyrazole
7 (cf. lit.2) (Scheme 3).¶ Compound 7, being less soluble in
water than 1, precipitates during the preparation of 1.
the protons of NHMe and carbon atoms C3 (d 140.80 ppm) and
C5 (d 133.82 ppm). These data, together with the chemical shift
of C4 (d 130.87 ppm) and the absence of spin-coupling inter-
action of NHMe with N1Me in the NOESY spectrum unambi-
guously show that the NHMe fragment is attached to the
4-position of the pyrazole ring of the product 8. This means that
in the parent compound 4b this group was also at the 4-position.
The structure of 4a was confirmed by its independent syn-
thesis through alkali hydrolysis of carbamate 96,7 (Scheme 4).‡
NHCO2Me
NO2
NH2
i, ii
O2N
O2N
NO2
X
X
N
NH
N
NH
O2N
NO2
O2N
NO2
i
9
4a
N
NH
N N
Scheme 4 Reagents and conditions: i, KOH (3 equiv.)/H2O, 70–90 °C,
7 h; ii, 20% H2SO4.
Me
1 X = NO2
4b X = NHMe
7 X = NO2
8 X = NHMe
Online Supplementary Materials
Scheme 3 Reagents and conditions: i, Me2SO4 (1.5 equiv.)–NaHCO3
(2 equiv.), H2O, room temperature, 7 h.
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2010.09.003.
References
§
Synthesis of 3,5-dinitro-4-SR-1H-pyrazoles 5a–f (general procedure).
To the solution of trinitropyrazole 1 (0.61 g, 3 mmol) in water (10 ml),
NaOH (0.24 g, 6 mmol) was added, and the mixture was stirred for
10 min, then the appropriate thiol (3.6 mmol) was slowly added. The
stirring was continued for 3 h at room temperature, then the mixture was
acidified with 20% H2SO4 to pH 1. The precipitate formed was filtered
off, dried and crystallized from EtOH–H2O.
1 I. L. Dalinger, G. P. Popova, I. A. Vatsadze, T. K. Shkineva and S. A.
Shevelev, Izv. Akad. Nauk, Ser. Khim., 2009, 2120 (Russ. Chem. Bull.,
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3 J. Catalan, J. L. Abband and J. Elguero, Adv. Heterocycl. Chem., 1987,
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and T. I. Cherkasova, Tetrahedron Lett., 2001, 42, 8539; (d) V. V. Rozhkov,
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6 V. M. Vinogradov, T. I. Cherkasova, I. L. Dalinger and S. A. Shevelev, Izv.
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5a: yield 70%, mp 92–93 °C. 1H NMR, d: 1.15 (t, 3H), 2.95 (q, 2H).
13C NMR, d: 14.45, 28.85, 107.54 (C4), 151.62 (C3, C5).
5b: yield 98%, mp 155–156 °C. 1H NMR, d: 7.35 (m, 5H). 13C NMR,
d: 105.13 (C4), 127.05, 128.15, 129.33, 133.82, 151.58 (C3, C5).
5c: yield 91%, mp 136–137 °C. 1H NMR, d: 7.17 (d, 2H), 7.45 (d, 2H).
13C NMR, d: 103.81 (C4), 119.80, 129.83, 132.02, 133.92, 152.10 (C3, C5).
5d: yield 85%, mp 138–139 °C. 1H NMR, d: 7.15 (d, 2H), 7.45 (d, 2H).
13C NMR, d: 103.88 (C4), 119.88, 129.90, 132.02, 133.81, 151.91 (C3, C5).
5e: yield 95%, mp 166–167 °C. 1H NMR, d: 4.23 (s, 2H), 7.15 (d, 2H),
7.39 (d, 2H). 13C NMR, d: 38.19, 105.77 (C4), 128.40, 130.68, 131.15,
136.00, 152.32 (C3, C5).
1
5f: yield 78%, mp 114–115 °C. H NMR, d: 3.72 (s, 2H). 13C NMR,
d: 36.13, 106.30 (C4), 151.90 (C3, C5), 170.34.
¶
For the synthesis and characteristics of compounds 6–8, see Online
Supplementary Materials.
Received: 28th April 2010; Com. 10/3516
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