Synthesis and structure analysis of N1,N4,3,6- Tetramethyl-N1,N4-diphenyl-1,4-dihydro-1,2,4,5-tetrazine- 1,4-dicarboxamide

Article abstract of DOI:10.3184/174751912X13305517249355

N¹,N⁴,3,6-Tetramethyl-N¹,N ⁴-diphenyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboxamide was prepared from 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine, bis(trichloromethyl) carbonate and N-methylaniline. Its structure was confirmed by single-crystal X-ray diffraction. This reaction yields the title compound rather than N ¹,N²,3,6-tetramethyl-N¹,N²-diphenyl- 1,2-dihydro-1,2,4,5-tetrazine-1,2-dicarboxamide. The central tetrazine ring of the title compound exhibits a boat conformation and is therefore not homoaromatic.

Full text of DOI:10.3184/174751912X13305517249355

178 RESEARCH PAPER
MARCH, 178–180
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis and structure analysis of N1,N4,3,6-tetramethyl-N1,N4-diphenyl-
1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboxamide
Guo-Wu Rao*, Qi Li and Zhen-Guo Zhao
College of Pharmaceutical Science, Zhejiang University ofTechnology, Hangzhou, 310014, P. R. China
N1,N4,3,6-Tetramethyl-N1,N4-diphenyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboxamide was prepared from 3,6-dimethyl-
1,6-dihydro-1,2,4,5-tetrazine, bis(trichloromethyl) carbonate and N-methylaniline. Its structure was confirmed
by single-crystal X-ray diffraction. This reaction yields the title compound rather than N1,N2,3,6-tetramethyl-N1,N2-
diphenyl-1,2-dihydro-1,2,4,5-tetrazine-1,2- dicarboxamide. The central tetrazine ring of the title compound exhibits a
boat conformation and is therefore not homoaromatic.
Keywords: tetrazine, X-ray diffraction, calculation, boat conformation
1,2,4,5-Tetrazine derivatives have good reactivities,1,2 and have
been widely used in organic synthetic chemistry and medicinal
chemistry.3–8 Dihydro-1,2,4,5-tetrazine has four isomers,
namely 1,2-, 1,4-, 1,6- and 3,6-dihydro-1,2,4,5-tetrazine.
Homoaromatic structures have been demonstrated by X-ray
diffraction in the 1,6-dihydro structures.9 There still seems to
be some doubt as to whether the 1,4-dihydro structures have
homoaromaticity. For example, X-ray diffraction was reported
to show that 3,6-bis(4-chlorobenzyl)-1,4-dihydro-1,2,4,5-tet-
razine has an obvious chair conformation without a homoaromatic
structure,10 but 1,3,4,6-tetramethyl-1,4-dihydro-1,2,4,5-tetra-
zine has been analysed by X-ray diffraction and a possible
homoaromatic structure was identified.11 There seems to be
confusion over the structures of 1,2- and 1,4-dihydro-1,2,4,5-
tetrazine isomers, and the same compound is often formulated
as both structures. In most cases, the dihydro structure, which
would be the first reaction product, is presented. Some scien-
tists believe that rearrangement can occur between 1,2- and
1,4-dihydro-1,2,4,5-tetrazine isomers.3
The single-crystal structure of compound 1 was determined
by X-ray crystallography. The molecular structure of com-
pound 1 is illustrated in Fig.1. Selected bond lengths are
listed in Table 1. In the molecule, the N2=C3 [1.282(3) Å] and
N5=C6 [1.272(3) Å] bonds correspond to typical double bonds
of C=N, and the C3–N4 [1.394(3) Å], N4–N5 [1.421(2) Å],
C6–N1 [1.396(3) Å] and N1–N2 [1.434(3) Å] bond lengths
correspond to typical single bonds. Therefore, the tetrazine
ring is the 1,4-dihydro structure with the N-substituted groups
at the 1,4-positions and not the 1,2-positions, the compound
being N1,N4,3,6-tetramethyl-N1,N4-diphenyl-1,2,4,5-tetrazine-
1,4-dicarboxamide (1), rather than N1,N2,3,6-tetramethyl-N1,
N2-diphenyl- 1,2,4,5-tetrazine-1,2-dicarboxamide (2). So the
product of the reaction of 3,6-dimethyl-1,6-dihydro-1,2,4,5-
tetrazine, BTC and N-methylaniline has the 1,4-dicarboxamide
structure rather than the 1,2-dicarboxamide structure.
In a continuation of our work on the structure–activity rela-
tionship of 1,2,4,5-tetrazine derivatives,10,12,13 we have obtained
a yellow crystalline compound that was the product of the
reaction of 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine, bis
(trichloromethyl) carbonate (BTC) and N-methylaniline. The
route of synthesis is shown in Scheme 1. The intermediate
raw material of 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine
was prepared according to literature methods.14–16 However,
IR, NMR, and MS studies failed to confirm whether the substi-
tuted groups of the nitrogen are located at the 1,4 or 1,2 posi-
tion (compound 1 or 2). Their structures were confirmed by
single crystal X-ray diffraction.
Fig. 1 The crystal structure of 1, shown with 30% probability
displacement ellipsoids.
Scheme 1 Route of synthesis.
* Correspondent. E-mail: rgw@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 179
Table 1 Selected bond lengths (Å)
As shown in the packing of compound 1 (Fig. 2), there exist
intramolecular hydrogen contacts (Table 3). The C–H···N and
C–H···O type of intramolecular interaction play major role in
stabilising the molecules in the unit cell.
Bond lengths
N1–N2
C3–N4
N5–C6
1.434(3)
1.394(3)
1.272(3)
N2-C3
N4-N5
C6-N1
1.282(3)
1.421(2)
1.396(3)
Experimental
Melting points were determined on a X-4 melting point apparatus and
uncorrected. IR spectra were taken on a Thermo Nicolet Avatar 370
FT-IR spectrophotometer (KBr pellets). H spectra were recorded on a
Bruker Avance (500M) spectrometer. MS spectra were obtained on a
Thermo Scientific ITQ 1100TM mass spectrometer.
Table 2 Least-squares plane
Orthonormal 7.8212 (43) x + 3.6127 (182) y + 7.0675 (156) z
equation of
Plane1
= 6.3706 (100)
N1,N4,3,6-tetramethyl-N1,N4-diphenyl-1,2,4,5-tetrazine-1,4-dicar-
boxamide (1): Bis(trichloromethyl) carbonate (5.198 g, 17.5 mmol)
was dissolved in CHCl3 (50 mL) with magnetic stirring, the solution
of 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (1.472 g, 13.1 mmol)
and 4-dimethylamino pryidine (0.656 g, 5.4 mmol) in CHCl3 (60 mL)
was added dropwise with stirring at 0 °C. Then the mixture was
allowed to reach room temperature and subsequently refluxed for 8 h.
A solution of N-methylaniline (5.198 g, 48.5 mmol) and CHCl3
(30 mL) was added dropwise with stirring at 5 °C. The mixture was
refluxed for 44h and washed with water. The solvent was removed
in vacuo. The residue was purified by flash column chromatography
on silica gel using petroleum ether/ethyl acetate (15:1, v/v) as eluent
to afford compound 1 (1.547 g, yield 31.1%) as a yellow solid. A
solution of the compound in ethanol was concentrated gradually at
Atom
N2
C3
N5
C6
0.0221 (10) −0.0221 (10) 0.0223 (10) −0.0222 (10)
In compound 1, the atoms N2, C3, N5 and C6 are coplanar,
with the largest deviation from the N2/C3/N5/C6 plane (Plane
1) being 0.0223 (10) Å for atom N5. The least-squares plane is
listed in Table 2. The adjacent N1 and N4 atoms deviate from
plane 1 by –0.4295 (28) and –0.4168 (28) Å, respectively. The
dihedral angle between plane 1 and the N1/N2/C6 plane is
34.43 (18)°, and between plane 1 and the N4/N5/C3 plane is
33.67 (16)°. The central six-member ring of compound 1, the
tetrazine ring, has an obvious boat conformation and is there-
fore not homoaromatic. The dihedral angles between the N2/
C3/N5/C6 plane and the two phenyl rings of the C9/C10/C11/
C12/C13/C14 and C15/C16/C17/C18/C19/C20 planes are
68.84 (10) and 46.14 (11)°, respectively. And two phenyl rings
form a dihedral angle of 79.78 (9)°.
Table 3 Hydrogen bonds bond lengths (Å) and angles (°)
Donor–H···Acceptor
D–H
H···A
D···A
D–H···A
C1–H1A···N6
C2–H2A···O1
C7–H7C···N2
0.96
0.96
0.96
2.59
2.09
2.52
3.161(3)
2.797(3)
3.075(3)
118.6
128.8
117.1
Fig. 2 A portion of the crystal packing of 1. Hydrogen bonds are shown as dashed lines. H atoms not involved in hydrogen bonding
are omitted for clarity.

180 JOURNAL OF CHEMICAL RESEARCH 2012
room temperature to afford yellow bars which are suitable for X-ray
diffraction. M.p. 121–124 °C. IR (KBr, cm−1): 3445, 1706, 1687,
1621, 1436, 1391, 1112, 1064, 950. H NMR (500 MHz, CDCl3) δ:
given isotropic displacement parameters equal to 1.2 (or 1.5 for methyl
H atoms) times the equivalent isotropic displacement parameters of
their parent atoms, and C–H distances were restrained to 0.96 Å for
methyl H atoms and 0.93 Å for phenyl H atoms, while N–H distances
were set to 0.86 Å. Full crystallographic details have been deposited
at the Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 863916. Copies of available material can
be obtained, free of charge, on application to the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223 336033 or
E-mail: deposit@ccdc.cam.ac.uk).
1
7.34 (t, J = 8 Hz, 4H, Ph), 7.23 (d, J = 7.5 Hz, 2H, Ph), 7.089–7.107
(m, 4H, Ph), 3.296(s, 6H, -NCH3), 1.957(s, 6H, CH3). MS (EI): m/z:
378 [M]+. MS (ESI): m/z: 379 [M+H]+, 401 [M+Na]+. HRMS (ESI):
m/z [M+H]+ Calcd for C20H23N6O2: 379.1882; found: 379.1891.
Crystal data of compound 1: A yellow bar of dimensions 0.40 ×
0.26 × 0.22 mm3 was used for data collection with a Bruker SMART
CCD area-detector diffractometer with graphite monochromated Mo
Kα radiation (λ = 0.71073 Å). A summary of crystal data is presented
in Table 4.
The structure was solved by direct method procedures as
implemented in the SHELXS9717 program. The positions of all the
non-hydrogen atoms were included in the full-matrix least-squares
refinement using the SHELXL9718 program. H atoms were added at
calculated positions and refined using a riding model. H atoms were
The authors are very grateful to the National Natural Science
Foundation of China (No. 20802069) and the Natural Science
Foundation of Zhejiang Province (No.Y2090985) for financial
support.
Received 23 January 2012; accepted 15 February 2012
Paper 1201125 doi: 10.3184/174751912X13305517249355
Published online: 22 March 2012
Table 4 Crystal data and structure refinement
References
Chemical formula
C20H22N6O2
1
2
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378.44
3
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b = 12.818(2) Å
c = 16.669(3) Å
1941.6(6)
7
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–11/12, –10/17, –19/21
11689/4441 (Rint = 0.0270)
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Reflections collected/unique
Absorption correction
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Extinction coefficient
Goodness of fit on F2
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R indices (all data)
0.981, 0.965
4441/0/254
0.028(3)
1.044
R1 = 0.0531, wR2 = 0.1385
R1 = 0.0627, wR2 = 0.1450
0.306, –0.257
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Structures. University of Göttingen, Germany, 1997.
Largest diff. peak and hole (e Å−3)

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