Synthesis and spectroscopic studies of trans-bis-(3,5-dimethyl-4-nitrosopyrazole) dimer

Article abstract of DOI:10.1016/j.tetlet.2007.05.146

Bis-(3,5-dimethyl-4-nitrosopyrazole) dimer was prepared by reaction of acetyl acetone with nitrous acid and condensation with hydrazine. Spectroscopic techniques, including IR, UV, ¹H NMR, and ¹³C NMR, and CHN analysis were used to identify the product.

Full text of DOI:10.1016/j.tetlet.2007.05.146

Tetrahedron Letters 48 (2007) 5547–5550
Synthesis and spectroscopic studies of
trans-bis-(3,5-dimethyl-4-nitrosopyrazole) dimer
Zeki A. Nasir Al-Shamkhani and Ali Hashem Essa*
Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
Received 3 March 2007; revised 19 April 2007; accepted 24 May 2007
Available online 31 May 2007
Abstract—Bis-(3,5-dimethyl-4-nitrosopyrazole) dimer was prepared by reaction of acetyl acetone with nitrous acid and condensa-
tion with hydrazine. Spectroscopic techniques, including IR, UV, 1H NMR, and 13C NMR, and CHN analysis were used to identify
the product.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Optically active nitroso compounds and nitrones have
played significant roles in organic chemistry due to their
broad utility, serving both as units for many biologically
active compounds and as important chiral ligands or
chiral auxiliaries for asymmetric synthesis.1
state, the temperature and, where appropriate, the sol-
vent. In contrast to the extensive investigations on mole-
cules containing one nitroso group 1 and dimers 2 and
3, relatively little attention has been directed to the
chemistry of molecules containing two independent
monomeric nitroso groups. There is little, if any,
experimental evidence for dinitroso alkanes, but it is
well known that 1,4-dichloro-1,4-dinitrosocyclohexane
can exist both as a stable trans-compound with two
monomeric N@O groups 4 and as the internal cis-dimer
5.1 The cis-dimer may be characterized as an azodioxide
compound or, more correctly, as a diazene-1,2-dioxide.
Generally, the trans-dimer is more stable than the cis-
dimer at room temperature in crystalline form or in solu-
tion. In general, trans-dimers are converted to cis-dimers
by UV irradiation while heat isomerizes the cis-dimers
to the trans-dimers.2,3
Nitroso compounds and nitrones can exist in the mono-
meric form 1 and in the cis- and trans-dimeric forms 2
and 3, respectively.1
R
R
N
1
O
O
R
O
R
O
N
N
N
N
R
O
3
2
N
O
O
O
Although nitrosopyrazoles have been known for over 50
years,4 relatively little spectroscopic information is avail-
able being confined to a study of the electron absorption
spectrum of 3,5-dimethyl-4-nitrosopyrazole in water and
dilute sodium hydroxide;5 4-nitrosopyrazole has also
been reported.6,7 In, addition, a small number of nitroso-
pyrazoles form nitroxides when used as free radical
traps.8 Extensive studies of the radiosensitivity of pyraz-
oles have revealed a number of biochemical and biolog-
ical effects associated with their reductive metabolism.9
Cl
Cl
N
N
Cl
Cl
O
N
4
5
The monomers are green-blue in color and the dimers
are colorless. The relative stabilities of the three forms
are dependent upon the structure of R, the physical
Nitrones and nitroso compounds are used in 1,3-dipolar
cycloaddition reactions to synthesize compounds having
interesting pharmacological activities and for the prepa-
ration of many stereochemically defined five-membered
Keywords: Nitroso compounds; Heterocyclic dimer; Bis-(3,5-dimethyl-
4-nitrosopyrazole) dimer; Semi-empirical AM1 and PM3 methods.
*
Corresponding author. Tel.: +964 7801255033;
alihashemalyunis@yahoo.com
e-mail:
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.146

5548
Z. A. N. Al-Shamkhani, A. H. Essa / Tetrahedron Letters 48 (2007) 5547–5550
heterocycles.10–15 Due to their importance, we report
herein the preparation of a new nitroso dimer.
1.6
1.4
1.2
1
Of further interest is a comparison between 3,5-di-
methyl-4-nitrosopyrazole and 2,4,6-trimethylnitroso
benzene16 with regard to the steric effects of the bulky
groups upon the NMR chemical shift of the C–NO
carbon. The geometry of the five-membered ring of the
nitrosopyrazole implies that the steric hindrance
between the nitroso group and the adjacent methyl
groups is reduced compared with that for the similarly
hindered nitroso benzene. The 13C substituent shift of
the C–NO group is increased considerably when it is
flanked by bulky tert-butyl groups attached to the benz-
ene ring.17
0.8
0.6
0.4
0.2
0
200
240
280
320
360
400
Wavelength (nm)
Figure 1. UV spectrum (CHCl3) of trans-bis-(3,5-dimethyl-4-nitroso-
pyrazole) dimer.
In our recent investigations18,19 on the preparation of
nitroso compounds, we demonstrated that the synthesis
of these compounds in the solid state could generate persis-
tent nitroso dimers which can be detected by electronic
absorption, infrared and nuclear magnetic resonance
spectroscopy. The synthesis of bis-(3,5-dimethyl-4-
nitrosopyrazole) dimer is shown in Scheme 1.
pair localized on the nitrogen atom. This transition dis-
appears when the nitrogen lone-pair of the monomer
was used to form the N@N bond on dimerization.21
Many groups22–24 have assigned the infrared N–O
stretching frequencies of cis-and trans-nitroso dimers.
Typically, the N–O stretch of cis-dimers appears as a
strong double band absorption in the 1180–1320 cmÀ1
range, whilst trans-dimers exhibit a single strong stretch-
ing absorption in the same range. The IR spectral
assignments are based on the CNOCNO grouping of
the dimer and conform with group theory.18 The infra-
red spectrum of the bis-(3,5-dimethyl-4-nitrosopyrazole)
dimer prepared herein shows a single stretching fre-
quency at 1220 cmÀ1 for the N–O group thus confirming
that the solid nitroso pyrazole dimer existed in the trans
form.
The trans-bis-(3,5-dimethyl-4-nitrosopyrazole) dimer
was prepared by treatment of acetylacetone with nitrous
acid to give an oxime which was then condensed with
hydrazine hydrate resulting in a white crystalline solid
in 42% yield.
The dimer dissolved on heating in ethanol to give an
almost colorless solution which became green on cooling.
Heating the solution dissociated the solid dimer to the
monomer.
The existence of the trans-bis-(3,5-dimethyl-4-nitroso-
pyrazole) dimer in the solid phase or in solution was
proved by studying its electronic and infrared spectra.
The electronic absorption spectra were recorded in chlo-
roform at room temperature and showed that the dimer
exhibited two (p–p*) transition bands, the first transition
band at 296 nm being ascribable to the dimeric grouping
(N2O2), and the other transition at 254 nm being due to
the C@C and C@N bonds, Figure 1.
The CNOCNO group of the dimer skeleton has essen-
tially C2h symmetry and therefore the bu skeletal fre-
quencies for antisymmetric N–O and C–N stretching
vibrations are for the cis-dimer. Due to the basic skele-
ton C2h symmetry both the A1 vibrations, which include
the symmetric N–O and C–N stretching modes and the
N–N stretching mode, and also the b1 vibration, which
includes the antisymmetric N–O and C–N stretches,
are all expected to absorb above 900 cmÀ1 in the infra-
red region.
Analysis of the dimeric p–p* transition revealed that a
comparison between the electronic configuration of the
monomers and the dimers suggested that the dimeriza-
tion process required organization of the electron distri-
bution in the R–NO subunit. Experimental evidence,
indicated that this does indeed happen.20
The conformation of the trans-bis-(3,5-dimethyl-4-
nitrosopyrazole) dimer was further confirmed by analy-
sis of the proton resonance signals.20
In the 1H NMR spectrum, two resonances were
observed at d 2.34 and d 7.20 ppm. That at d 2.34 ppm
The color of the monomers in solution might be due to a
weak n–p* transition, which involved an electron lone-
6
O
O
3
N2
O
O
OH
NH2NH2 / H2O
NaNO2
HCl
N
4
N
N
NH
N
1
5
HN
O
O
7
Scheme 1.

Z. A. N. Al-Shamkhani, A. H. Essa / Tetrahedron Letters 48 (2007) 5547–5550
5549
O
O
N
1.22
N
N
1.18
N
1.34
1.20
106.30
1.42
18.42
1.46
1.38
HN
1.13
HN
1.50
NH
1.39
NH
1.50
N
5.87
N
1.34
1.35
1.43
1.14
117.30
171.14
N
N
1.62
1.16
O
O
PM3
AM1
˚
˚
Figure 2. Structures of bis-(3,5-dimethyl-4-nitrosopyrazole) with bond lengths shown in Angstroms (A) and bond angles in degrees (ꢁ) computed
using the semi-empirical AM1 and PM3 methods.
was due to the C-6 and C-7 methyl protons, which
exist in analogous chemical environments. The sec-
ond resonance can be attributed to the N-1 amino
protons.
References and notes
1. Anderson, L.; Cameron, M.; Gowenlock, B. G.; McEwen,
I. J. J. Chem. Soc., Perkin Trans. 2 1992, 243.
2. Fletcher, D. A.; Gowenlock, B. G.; Orrell, K. G. J. Chem.
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3. Fletcher, D. A.; Gowenlock, B. G.; Orrell, K. G.; Sik, V.
J. Chem. Soc., Perkin Trans. 2 1995, 191.
4. Bock, W. P.; Lorentz, G.; Trap, P. J. Liebigs. Ann. Chem.
1952, 325, 129.
5. Habraken, C. L. Rec. Trav. Chem. Pays-Bas. 1986, 87,
1242.
6. Boyed, G. V.; Norris, T. J. Chem. Soc., Perkin Trans. 1
1974, 1028.
In the 13C NMR spectrum of the trans-compound, three
resonances were observed. These signals were due to the
five carbon atoms, C-6, C-7 = 28.48 ppm, C-3, C-5 =
86.33 ppm, and C-4 = 132.59 ppm. 13C NMR spectros-
copy has provided interesting structural information
on C-nitroso compounds, and the large difference
(<20 ppm) between the C–NO and C–N2O2–C reso-
nances clearly allows the prediction of monomeric
N–O or dimeric N2O2 modes in the solid state.25,26
7. Habraken, C. L.; Beenakker, C. I.; M. Brusec, J. J.
Heterocycl. Chem.. 1972, 9, 939.
8. Mathew, L.; Osei-Twan, E. W.; Warentin, J. Can. J.
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Chem. 1988, 66, 3044.
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11. Parhi, A. K.; Franck, R. W. Org. Lett. 2004, 6, 3063.
12. Stappers, F.; Broeckx, R.; Leurs, S.; Van Den Bergh, L.;
Agten, J.; Lambrechts, A.; Van den Heuvel, D.; De
Smaele, D. Org. Process Res. Dev. 2002, 6, 911.
13. Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T.
Org. Lett. 2007, 9, 207.
Figure 2 displays the geometry optimization of bis-(3,5-
dimethyl-4-nitrosopyrazole) using semi-empirical AM1
and PM3 methods.27 The figures show bond lengths in
Angstroms (A) and bond angles in degrees (ꢁ).
˚
Preparation of trans-bis-(3,5-dimethyl-4-nitrosopyraz-
ole) dimer: Acetyl acetone (10 g, 0.1 mol) was added to
a solution of concentrated hydrochloric acid in water
(9 ml HCl in 50 ml H2O), and cooled in ice to 8 ꢁC.
Sodium nitrite (7.1 g, 0.1 mol) in 20 ml of water was added
dropwise and the mixture was allowed to stand for
20 min. Hydrazine hydrate (5.4 g, 0.1 mol) was added
with stirring, which resulted in immediate formation of
a white crystalline precipitate of trans-bis-(3,5-di-
methyl-4-nitrosopyrazole) dimer. This was filtered off,
washed with ethanol, dried and then recrystallized from
chloroform. Melting point (mp) = 114–116 ꢁC, CHN
analysis for C10H14N6O2 Calcd: C, 47.99; H, 5.64; N,
33.59%. Found: C, 47.52; H, 5.52; N, 33.50. UV
(CHCl3), kmax 254 nm and 296 nm. IRm = 3103 (N–H),
2896 (CH3), 1625 (C@N), 1508 (C@C), 1309 (N@N),
´
14. Topic, D.; Aschwanden, P.; Fa¨ssler, R.; Carreira, E. M.
Org. Lett. 2005, 7, 5329.
15. Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J.
Am. Chem. Soc. 1998, 120, 12355.
16. White, J. D.; Hansen, J. D. J. Am. Chem. Soc. 2002, 124,
4950.
17. Gowenlock, B. G.; Cameron, M.; Boyed, A. S.; Al-Tahou,
B. M.; McKenna, P. Anal. J. Chem. 1994, 72, 514.
18. Al-Shamkhani, Z. A. J. Basrah Res. 2002, 28, 81.
19. Al-Shamkhani, Z. A. J. Basrah Res. 2006, 32, 88.
20. Al-Shamkhani, Z. A., M.Sc. Thesis, University of Basrah.,
2000.
21. Luttke, W.; Skanke, P. N.; Traetteberg, M. Theor. Chem.
Acta. 2004, 87, 321.
22. Witanowski, M.; Biodrzycka, Z.; Webb, G. A. Mag.
Reson. Chem. 1996, 34, 233.
1
1220 (N–O), 1093 (C–N) cmÀ1. H NMR (400 MHz,
CDCl3) dH = 2.34 (6H, s, 2 · CH3) and 7.20 (2H, s,
2 · NH) ppm. 13C NMR (100 MHz, CDCl3) dC = 28.48,
86.33 and 132.59 ppm.
23. Gowenlock, B. G.; King, B.; Pfaband, J.; Witanowski, M.
J. Chem. Soc., Perkin Trans. 2 1997, 483.
24. Gowenlock, B. G.; Batt, L. J. Mol. Struct. Theochem.
1998, 103, 454.
25. Fletcher, D.; Gowenlock, B. G.; Orrell, K. G.; Sik, V.
Magn. Reson. Chem. 1995, 35, 569.
Acknowledgment
We wish to express thanks to Professor B. G. Gowenlok,
School of Chemistry, the University of Exeter for carry-
ing out NMR analysis.
26. Anderson, L.; Boyed, A. S.; Cameron, M.; Gowenlock, B.
G.; Higgnison, C. M.; McEwen, I. J.; Smith, J. P. J. Chem.
Res. 1994, 245.

5550
Z. A. N. Al-Shamkhani, A. H. Essa / Tetrahedron Letters 48 (2007) 5547–5550
27. Semi-empirical self-consistent-field molecular orbital
(SCF-MO) method at AM1 (Dewar, M. J. S.; Zoebisch,
E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. Soc.
1985, 107, 3902) and PM3 (Stewart, J. J. P. J. Comput.
Chem. 1989, 10, 209) levels within restricted Hartree–Fock
(RHF) (Roothaan, C. C. J. Rev. Mod. Phys. 1951, 23, 69).
Formalism has been considered to optimize fully the
geometry of the bis-(3,5-dimethyl-4-nitrosopyrazole)
dimer in its ground state. Geometry optimization was
carried out by using a conjugate gradient method (Polak–
Ribiere algorithm) (Fletcher, P., Practical Methods of
Optimization, Wiley, New York, 1990). The SCF conver-
gence was set at 0.001 kcal/mol and the RMS gradient was
˚
set to 0.001 kcal/(A mol) in the calculations. We per-
formed all the calculations using the HyperChem-7
program. (HyperchemTM release 7.52. Windows Molecu-
lar Modeling System, Hypercube, and Autodesk, Devel-
oped by Hypercube).