Synthesis and characterization of 2,3,5,6-tetraphenylpyrazine-N, N-dioxide: New nitrone dimer species

Article abstract of DOI:10.3987/COM-08-11382

The synthesis, characterization and physical properties of 2,3,5,6-tetraphenylpyrazine-N,N-dioxide presently are reported. A specific reduction mechanism of an oxime using zinc with NH₄Cl to yield hydroxylamine was performed. This was followed by a condensation reaction with sulfuric acid that leads to 2,3,5,6-tetraphenylpyrazine-N,N-dioxide. The product was characterized by means of IR, UV,¹H-NMR and¹³C-NMR spectroscopy which were complemented by theoretical computations. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11382

HETEROCYCLES, Vol. 75, No. 9, 2008
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HETEROCYCLES, Vol. 75, No. 9, 2008, pp. 2235 - 2242. © The Japan Institute of Heterocyclic Chemistry
Received, 7th March, 2008, Accepted, 17th April, 2008, Published online, 21st April, 2008. COM-08-11382
SYNTHESIS AND CHARACTERIZATION OF 2,3,5,6-TETRAPHENYL-
PYRAZINE-N, N-DIOXIDE: NEW NITRONE DIMER SPECIES
Ali Hashem Essa,a* Zeki A. Nasir Al-Shamkhani,a Abraham F. Jalbout,b and
Ali Jameel Hameeda
*a Department of Chemistry, College of Science, University of Basrah, Basrah,
Iraq
b Instituto de Quimica, Universidad Nacional Autonoma de Mexico, Mexico D.F.
Email: alihashemalyunis@yahoo.com
Tel: +9647801255033
Abstract – The synthesis, characterization and physical properties of
2,3,5,6-tetraphenylpyrazine-N,N-dioxide presently are reported. A specific
reduction mechanism of an oxime using zinc with NH4Cl to yield
hydroxylamine was performed. This was followed by a condensation reaction
with sulfuric acid that leads to 2,3,5,6-tetraphenylpyrazine-N,N-dioxide. The
1
product was characterized by means of IR, UV, H-NMR and 13C-NMR
spectroscopy which were complemented by theoretical computations.
INTRODUCTION
The chemistry of N-oxides has been the focus of research in several years.1 A wide range of mono, di and
tri substituted derivatives of N-oxides have been prepared and physically characterized. The majority of
these are isolated colorless solids or oily compounds. It soon became known that the color solids
produced were aliphatic. On the contrary, the oily compounds were indeed aromatic. Further IR
measurements demonstrate the existence to different forms of N-oxide. 2,3 The isomeric forms synthesized
are identical to the cis and trans alkenes. In relation to the N-substituted aldimines, the structure a in
Scheme 1 (R2 = H, X = alkyl or aryl) has the hydrogen atom on the same side of the double bond as the
N-substituent which is thermodynamically more stable. This is designated as the anti isomer and the other
configuration (Scheme 1b, R2 = H, X = alkyl or aryl) is the less stable syn isomer.2

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HETEROCYCLES, Vol. 75, No. 9, 2008
R2
R1
R2
R1
N
N
X
X
a
b
(R2 smaller than R1)
Scheme 1
The nitrone structure is traditionally viewed as a resonance hybrid of three canonical forms4, 5 depicted in
Scheme 2. The most significant form (based on reactivity) is the extended carbonyl structure a. The
nitrones should be subject to electrophilic attack at the oxygen atom and nucleaphilic attack at the carbon
atom as is observed in the laboratory.
:
C
N
C
N
C
N
O
O
O
a
b
c
Scheme 2
Solutions of many organic N-oxide compounds (R – C = NÆ O) in organic solvents leads to interesting
behavior. In these solutions the (N Æ O) group is bonded to a carbon atom which depends on the nature
of the organic group (R), temperature and concentration.6
Scant spectroscopic information on the internal nitrone group in comparison to the external nitrone
group7 is available. In this work, we have prepared and analyzed the UV, IR and NMR spectra of 2,3,5,6-
tetraphenylpyrazine-N,N-dioxide.
The favored preparative protocol of 2,3,5,6-tetra phenyl pyrazine N,N-dioxide involves the condensation
of 2-hydroxybenziloxime with sulfuric acid as a catalyst. This reaction is based on converting the benzil
to benzildioxime then finally to 2-hydroxylamine benziloxime by a reduction scheme using zinc powder
and NH4Cl.
Recent spectroscopic evidence on substituted aromatic N-oxide compound has yielded information on the
effect of substitution nitrone.8 The ground and excited electronic states for both isomers of the nitrone
were identified from absorption spectra. What is interesting to note is the determination of the nature of
the bonding forces in the cis structure. This was performed to gain further insight into the rate of trans
formation.

HETEROCYCLES, Vol. 75, No. 9, 2008
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Various methods have been reported regarding the synthesis of aliphatic or aromatic N-oxide
compounds.9-11 Related species of this type were prepared by photolysis and oxidation of aldehydes
or ketones. Compounds resulting from such a procedure are identified as aldonitrones or kitonitrones
respectively.
The utility of hydroxylamine oxime condensation for the synthesis of nitrone (N-oxide) is not impaired by
its susceptibility to steric hindrance.12 This approach is exemplified by a standard method for the
synthesis of cyclic nitrone, and has been used with particular success for the general synthesis of the
synthetically important pyroline-N-oxide.
RESULTS AND DISCUSSION
The synthesis of 2,3,5,6-tetraphenylpyrazine-N,N-dioxide is represented in Scheme 3. The preparative
formation of an oxime is well known.13 Poor yields were obtained with sodium acetate in the diketone,
and we found it utile to compare this to the ketone. We obtained over 86% yields of oxime by using this
method. The reduction of dioxime carried out by the addition of freshly zinc powder to the mixture of
1,2-diphenylethane-1,2-dionedioxime and NH4Cl was successful.
O
N
N
O
5
6
4
2
1
N
N
N
N
O
O
H2SO4
NH4Cl / Zn
OH
OH
NH4OH / HCl
CH3CO2Na
OH
OH
3
1
2
3
Scheme 3
Acid catalyzed condensation with carbonyl compounds has been reported to result in the formation of
imidazole oxide derivatives.14,15 The acid catalyzed condensation occurs when hydroxylamine oxime is
treated with concentrated sulfuric acid. This reaction may involve the elimination of the hydroxylamine
along with an accompanying oxidation mechanism (the major product is the pyrazine-N,N-dioxide (Rf =
0.32)).
N-oxide is a white crystalline compound that dissolves in CHCl3 and acetone solvents. This
compound does not yield isomers in an aqueous acidic or basic medium. In contrast to the aromatic
N,N-dioxide, the whole aliphatic nitrones revealed no tendency to dimerize.16 The relative stability of
pyrazine-N,N-dioxide may therefore be related to conjugation with the aromatic rings. The stabilization of
the 1,2-ethanedinitrone N(O):CH.CH:NO group occurs only when the aromatic rings can become
coplanar with it.17 However, the nature of the dimerization oxidation remains to be explored.

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Elimination of hydroxylamine oxime (preformed by a suitable condensation reaction) leads to a crucial
step in a number of synthetic methods leading to nitrone. Perhaps the simplest and most general method
of this type is an extension of oxime formation by hydroxylamine oxime condensation. Nitrone formation
from a simple aromatic ketone is uncomplicated by the tendency of the product to undergo subsequent
dimer condensations.
The existence of synthesized molecules in either solution or solid state can be verified by electronic and
infrared spectra. In the current report, the electronic spectra were recorded at rt and exhibit two bands.
The first transition band (π- π*) is accounted to the double bond of an aryl residual but the other transition
(π - π*) is ascribable to an N-oxide group.
The substance was assigned to the dinitrone (N,N-dioxide) structure based on spectroscopic evidence.8
The value observed on the UV absorption maximum at 249 nm for the mono group is comparable to the
value of the di group which reaches a maximum of 295 nm (i.e 1,2-ethanedinitrone).8
Many groups8, 18 have assigned the N-O stretching frequency in the 1100-1300 cm-1 range as a strong
band. This IR assignment is based on the R group attached at imine group site.
The characteristic band in infrared spectrum of the pyrazine-N,N-dioxide compound at 1558 and 1228
cm-1 indicates the presence of the C=N and N-O groups respectively. The elemental composition suggests
the absence of two carbonyl groups and hydroxyl groups in the dimer species.
1
The H NMR spectrum exhibits two resonance regions 7.5 and 6.7 ppm, the first region of resonance
signals due to the proton of aromatic ring, which was analogous in chemical environment. The other
region is caused by CDCl3 solvent.
13C NMR spectroscopy has provided important information on the nature of the N-oxide compounds, that
yielded six lines. Four lines were generated by carbon atoms of the aromatic ring in addition to the two
lines of the cyclic pyrazine.19 The remainder of the lines were attributed to the CDCl3 solvent.
The geometry of the six membered ring of the pyrazine-N,N-dioxide implies that the steric hindrance of
the nitrone group be reduced. This effect is lower when compared with that for the hindrance observed in
nitroso benzene.20
COMPUTATIONAL STUDY
Some electronic details about the system considered is given in Table 1. The geometry optimization at the
AM1 and PM3 methods yields a non-planar structure as the stable form with C1 symmetry for
2,3,5,6-tetraphenylpyrazine-N,N-dioxide.
The calculated frontier bonding molecular orbitals (MO) of 2,3,5,6-tetraphenylpyrazine-N,N-dioxide
(HOMO shown in Figure 1) is largely localized on the NÆO fragment. The electronic character of 3 is
also of interest with respect to its reactivity, especially towards nucleophilic agents such as olefins.

HETEROCYCLES, Vol. 75, No. 9, 2008
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Table 1. Physical properties of 2,3,5,6-tetraphenyl pyrazine-N,N-dioxide.
O
N
N
O
Values
Quantity
AM1
154
77
PM3
154
77
DFT
218
109
328
540
No. of electrons
No. of doubly occupied levels
No. of total orbitals
148
-
148
-
No. of primitive gaussians
The calculated LUMO (electron acceptor orbital) of 2,3,5,6-tetraphenylpyrazine-N,N-dioxide is seen to be
substantially localized along the C-C axis of the pyrazine unit (Figure 1). Overall, the net positive charge
is calculated to be greatest at the nitrogen atom (+0.4). Complex 3 could thus be anticipated to act as an
N-centered electrophile. This means that the nitrone groups undergo cycloaddition reactions with alkenes,
a phenomenon observed in many practical reactions.20,21
HOMO
LUMO
Figure 1. DFT-calculated 3D HOMO (-0.158708eV) and LUMO (-0.074850eV) of 2,3,5,6-
tetraphenylpyrazine-N,N-dioxide
Isosurface of the electrostatic potential (ESP) for the molecule is shown in Figure 2. Dark (green) colors
indicate negative ESP regions and light (violet) colors indicate positive ESP regions. These figures
represent how the oxygen atoms have more negative ESP regions in comparison with other atoms. This
signifies that oxygen atoms undergo protonation reaction with acidic reagents.22

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HETEROCYCLES, Vol. 75, No. 9, 2008
a
b
Figure 2. Isosurface of the electrostatic potential in the spatial vicinity of the
2,3,5,6-tetraphenylpyrazine-N,N-dioxide. a: AM1 b: PM3 levels of theory.
EXPERIMENTAL
2.1. Preparation of 1,2-diphenylethane-1,2-dionedioxime compound 1.
Dissolve (0.7 g, 0.02 mol) of hydroxylamine hydrochloride and 4 g of crystallized sodium acetate in 10
°
mL of water in a small flask, warm the solution to about 40 C and added (2.1 g, 0.01 mol) of benzil.
Stopper the vessel securely with a cork and shake vigorously for a few minutes. The dioxime soon
separates as a crystalline solid, cool in ice and filtration. Wash with a little cold water. Re-crystallize from
light petroleum. mp 236-237 °C (decomp). (lit., 23 mp 238 °C).
2.2. Preparation of 2-Hydroxyamino-1,2-diphenylethanonoxime compound 2.
To a solution of EtOH (100 mL) in water (10 mL) was added 1,2-diphenylethane-1,2-dionedioxime (1.2
g, 0.05 mol) and NH4Cl (1.4 g, 0.02 mol). While the mixture was stirred, freshly activated zinc powder
(10.2 g) was added over 15 min. (the temperature rise to 45 °C). After 1 h solution was filtered and treated
with acetic acid to give the crystalline acetic acid salt, which could be readily regenerated to the free
white crystals of 2-hydroxyamino-1,2-diphenylethanonoxime mp 147-148 °C.
2.3. Preparation of 2,3,5,6-tetraphenylpyrazine- N,N-dioxide 3.
A finally crystals sample of 1.5 g 2-hydroxyamino-1,2-diphenylethanonoxime was introduce in a small
portions at a time to 10 mL of concentrated sulfuric acid at 0 °C with mechanical stirring. The slurry was
gradually warmed to ambient temperature and allowed to stir for 36 h, made basic with 2N NaOH
solution and extracted several times with EtOAc. Wished with light petroleum, afforded yellow oil
°
compound. Recrystallized from CHCl3. A white crystal of product was obtained. mp 262-264 C.
Elemantal analyses: Anal. Calcd for C28H20N2O2: C, 80.77; H, 4.81; N, 6.73%. Found: C, 81.15; H, 4.28;
N, 7.22%. Ultraviolet absorption in CHCl3 λ
297 and 252 nm. Infrared absorption (KBr, cm -1) 3001
max
1
(CH), 1641(C=C), 1558 (C=N), 1228(N-O), 1097(C-N). H NMR (400 MHz, CDCl3) δH (ppm) 7.5s

HETEROCYCLES, Vol. 75, No. 9, 2008
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(5H). 13C NMR (100 MHz, CDCl3) δC (ppm) 146 C1, 135 C2, 127 C3, 125 C4, 124 C5, 126 C6.
2.4. Spectrophotometric measurement
1H NMR and 13C NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer, 400.13 MHz
for proton and 100.13 MHz for carbon, in CDCl3 as a solvent. Infrared spectra were recorded on a
Shimadzu FTIR model 8400. Ultraviolet spectra were recorded on a Spectro Scan 80D UV-Visible
Spectrophotometer. Finally, CHN analysis was carried out on Shimadzu 8011.
2.5. Computational Methods
Geometry optimizations were carried using a conjugate gradient method (Polak-Ribiere algorithm)24 by
applying the semi-empirical molecular orbital (MO) theory at the level of Austin Model 1 (AM1) and the
PM3 model25,26 within the restricted Hartree-Fock (RHF). The convergence has been set to 0.001 kcal
mol-1. The AM1 and PM3 computations have been done on the hyperchem release 7.5 for Widows17
running on Windows XP Workstation in Pentium IV PC.
All of the Density Functional Theory (DFT) electronic structure calculations were performed using the
DMol25-28 numerical-based density-functional computer software implemented in the Materials Studio
Modeling 3.1 package from Accelrys, Inc. Geometrical optimizations and frequency calculations were
carried out with the B3LYP general-gradient potential approximation in conjunction with the
double-numerical plus diffusion basis set (all-electron core treatment) was employed (denoted as DND).
The calculations were performed with an SCF tolerance level of 1.0 X 10-6 and global orbital cutoffs of 5.5
angstroms.
ACKNOWLEDGEMENTS
The authors are grateful to Prof. B. G. Gowenlok, School of Chemistry, University of Exeter, for carrying
out the NMR spectra.
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