Synthesis and structure analysis of 1-propionyl-3,6-diphenyl-1,4-dihydro-1, 2,4,5-tetrazine

Article abstract of DOI:10.3184/174751913X13626783814049

1-Propionyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine was prepared from propionic anhydride and 3,6-diphenyl- 1,4(or 1,2)-dihydro-1,2,4,5-tetrazine, and its structure was determined by X-ray diffraction. This reaction yields the title compound rather tha

Full text of DOI:10.3184/174751913X13626783814049

JOURNAL OF CHEMICAL RESEARCH 2013
APRIL, 239–241
RESEARCH PAPER 239
Synthesis and structure analysis of 1-propionyl-3,6-diphenyl-1,4-dihydro-
1
,2,4,5-tetrazine
Guo-Wu Rao*, Jia-Bin Ni, Yu-Bo Fu and Hao Chen
College of Pharmaceutical Science, Zhejiang University ofTechnology, Hangzhou, 310014, P. R. China
1
1
-Propionyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine was prepared from propionic anhydride and 3,6-diphenyl-
,4(or 1,2)-dihydro-1,2,4,5-tetrazine, and its structure was determined by X-ray diffraction. This reaction yields the
title compound rather than 1-propionyl-3,6-diphenyl-1,2-dihydro-1,2,4,5-tetrazine. The central tetrazine ring of the
title compound exhibits a boat conformation and is not, therefore, homoaromatic.
Keywords: tetrazine, X-ray diffraction, boat conformation, 1-propionyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine
1
,2,4,5-Tetrazine derivatives have been widely used in medici-
a yellow crystalline compound that was the product of the
reaction of propionic anhydride and 3,6-diphenyl-1,4(or 1,2)-
dihydro-1,2,4,5-tetrazine (compound 1 or 2). The latter
1
–7
nal chemistry and organic synthetic chemistry. Dihydro-
1
3
,2,4,5-tetrazine has four isomers, namely 1,2-, 1,4-, 1,6- and
,6-dihydro-1,2,4,5-tetrazine. Homoaromatic structures have
9
was prepared according to the procedure of Rao et al. As
been demonstrated by X-ray diffraction in the 1,6-dihydro
structures. But there is still some doubt as to whether 1,4-
dihydro structures have homoaromaticity. For instance, X-ray
diffraction was reported to show that several 1,4-dihydro-
Scheme 1 shows, there may be two possible compounds, (3)
and (4), for the product. However, IR, NMR and MS studies
failed to prove whether the product has a homoaromatic struc-
ture and whether the hydrogen on the nitrogen is located at the
4 or 2 position. The structure of the product was confirmed by
single-crystal X-ray diffraction.
8
1
,2,4,5-tetrazine derivatives have an obvious boat conforma-
4
–7
tion without a homoaromatic structure, and 3,6-bis(4-chlo-
robenzyl)-1,4-dihydro-1,2,4,5-tetrazine have an obvious chair
conformation without a homoaromatic structure . But 1,3,4,6-
Two molecules forming the asymmetric unit of compound 3
are shown in Fig. 1. Selected bond lengths are listed in Table 2.
In the two molecules (Fig. 1), the N2=C3 [1.288(3) Å] and
N5=C6 [1.273(3) Å] bonds correspond to typical double bonds
of C=N, and the C3–N4 [1.374(3) Å], N4–N5 [1.387(3) Å],
C6–N1 [1.420(3) Å] and N1–N2 [1.430(3) Å] bond lengths
are typical for single bonds. The N6=C23 [1.283(3) Å] and
N8=C26 [1.274(3) Å] bonds correspond to typical double
bonds of C=N, and the C23-N7 [1.373(3) Å], N7–N8 [1.407(2)
Å], C26–N3 [1.415(3) Å] and N3–N6 [1.428(2) Å] bond
lengths are typical for single bonds. Therefore, the tetrazine
ring is the 1,4-dihydro structure with the N-substituted group
at the 1-position and the N-hydrogen at the 4- and not the
2-position, the compound being 1-propionyl-3,6-diphenyl-1,4-
dihydro-1,2,4,5-tetrazine, (3), rather than 1-propionyl-3,6-
diphenyl-1,2-dihydro-1,2,4,5-tetrazine, (4).
9
tetramethyl-1,4-dihydro-1,2,4,5-tetrazine was analysed by
1
0
X-ray diffraction and Bemis et al. deemed that this poten-
tially antiaromatic or homoaromatic ring system had a flat-
tened boat conformation with both N-methyls in equatorial
positions. Their dihedral angles and distances are listed in
Table 1. There seems to be considerable 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.
For example, the CAS number of both 3,6-diphenyl-1,4-dihy-
dro-1,2,4,5-tetrazine and 3,6-diphenyl-1,2-dihydro-1,2,4,5-
tetrazine is 14478-73-0. In most cases, the dihydro structure
which would be the initial reaction product is presented, or
the authors have formulated their compounds in the dihydro
structure which seemed to be the most accepted at that time.
Some believe that rearrangement can occur between 1,2- and
In compound 3, least-squares planes are listed in Table 3.
Atoms N2, C3, N5 and C6 are coplanar, with the largest devia-
tion from the plane (Plane 1) being –0.0225(11) Å for atom
N5. The adjacent N1 and N4 atoms deviate from plane 1 by
1
1
1,4-dihydro-1,2,4,5-tetrazine isomers.
In a continuation of our studies of structure–activity rela-
9
,12
tionships in 1,2,4,5-tetrazine derivatives, we have obtained
Table 1 The dihedral angles and distances
3
6
a
b
c
d
No.
I4
R1
CNHCO
R4
CNHCO
R /R
Dihedral angle /° Dihedral angle /°
Distance /Å
Distance /Å
(CH
3
)
3
(CH
3
)
3
CH
CH
Ph
Ph
3
33.77(27)
34.43(18)
34.04(13)
32.88(19)
43.03(34)
28.20(25)
34.30(18)
33.67(16)
28.35(13)
28.45(12)
43.03(34)
30.35(24)
0.4164(38)
–0.4295(28)
0.4291(24)
–0.4070(24)
0.5798(63)
0.3132(33)
0.4216(37)
–0.4168(28)
0.3403(23)
–0.3402(27)
–0.5798(63)
0.3388(33)
5
II
Ph(CH )NCO
m-CH OC CO
o-ClC CO
3
Ph(CH )NCO
3
3
6
III
3
6
H
4
H
H
H
7
IV
6 4
H
9
V
H
p-ClC
6 4 2
H CH
1
0
VI
CH
3
CH
3
CH
3
a
The dihedral angle between the N2/C3/N5/C6 plane and the N1/N2/C6 plane.
The dihedral angle between the N2/C3/N5/C6 plane and the N4/N5/C3 plane.
The distance of the adjacent N1 atom deviate from the N2/C3/N5/C6 plane.
The distance of the adjacent N4 atom deviate from the N2/C3/N5/C6 plane.
b
c
d
*
Correspondent. E-mail: rgw@zjut.edu.cn

2
40 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 1 Synthesis of 3.
Table 2 Selected bond lengths (Å)
Bond lengths
N1–N2
N2–C3
C3–N4
N4–N5
N5–C6
C6–N1
1.430(3)
1.288(3)
1.374(3)
1.387(3)
1.273(3)
1.420(3)
N3–N6
N6–C23
C23–N7
N7–N8
N8–C26
C26–N3
1.428(2)
1.283(3)
1.373(3)
1.407(2)
1.274(3)
1.415(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). NMR spectra were recorded
at 400 MHz on a Bruker Avance DMX400 spectrometer. Mass spectra
were obtained on a HP5989A mass spectrometer using EI. C, H and N
were analysed using a Carlo-Erba 1160 instrument.
Fig. 1 Themolecularstructureof3, shownwith30%probability
displacement ellipsoids.
1
-Propionyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (3): 3,6-
Diphenyl-1,4(or 1,2)-dihydro-1,2,4,5-tetrazine (1.2 g, 5.1 mmol),
prepared according to the procedure of Rao et al., was dissolved
in dichloromethane (20 mL) with stirring. Propionic anhydride (1.3 g,
9
0
.5013(32) and 0.3688(32) Å, respectively. The dihedral angle
between plane 1 and the N1/N2/C6 plane is 40.41(21)°, and
between plane 1 and the N4/N5/C3 plane is 31.18(18)°. Atoms
N6, C23, N8 and C26 are coplanar, with the largest deviation
from the plane (Plane 2) being 0.0157(11) Å for atom N8. The
adjacent N3 and N7 atoms deviate from plane 2 by –0.4537(32)
and –0.3804(30) Å, respectively. The dihedral angle between
plane 2 and the N3/N6/C26 plane is 36.64 (17)°, and between
plane 1 and the N7/N8/C23 plane is 31.26 (23)°. The differ-
ences in dihedral angles are presumably due to steric effects of
the substituents at the 1-position. The central tetrazine ring of
compound 3 exhibits an obvious boat conformation (Fig. 2)
and is not, therefore, homoaromatic.
1
0.0 mmol), pyridine (1 mL), and dichloromethane (20 mL) were
added to the mixture in an ice bath. The mixture was stirred at
The dihedral angles between plane 1 and the two phenyl
rings of the C5/C7/C8/C9/C10/C11 and C12/C13/C14/C15/
C16/C17 planes are 19.92(11) and 26.14(14)°, respectively.
The dihedral angle between the two phenyl rings of 3,6-
positions is 44.38(10)°. The dihedral angles between plane 2
and the two phenyl rings of the C21/C22/C24/C25/C27/C28
and C29/C30/C31/C32/C33/C34 planes are 24.05(12) and
3
6.73(13)°, respectively. The dihedral angle between the two
Fig. 2 A boat conformation of compound 3, shown with 10%
probability displacement ellipsoids.
phenyl rings of 3,6-positions is 60.52(10)°.

JOURNAL OF CHEMICAL RESEARCH 2013 241
Table 3 Least-squares planes
Orthonormal equation of Plane 1
Atom
6.7529(199) x + 3.4749(206) y –14.0858(58) z = 0.6407(100)
N2
C3
N5
C6
–
0.0222(11)
0.0223(11)
–0.0225(11)
0.0222(11)
Orthonormal equation of Plane 2
Atom
–7.9344(152) x + 6.2902(198) y + 13.0971(108) z = 1.2208(116)
N6
C23
N8
C26
0.0154(11)
–0.0156(11)
0.0157(11)
–0.0154(11)
room temperature for 22 h, washed with water, and dried with anhy-
area-detector diffractometer with graphite-monochromated Mo Kα
radiation (λ = 0.71073 Å). A summary of crystal data is presented in
Table 4.
drous MgSO . Solvent was removed in vacuo and the residue was
4
recrystallised from 95% ethanol to give the product 3 (1.0 g, 67.4%)
as a yellow solid. A solution of the compound in ethanol/ethyl acetate
The structure was solved by direct method procedures as imple-
13
(
4:1, v/v) was concentrated gradually at room temperature to afford
mented in SHELXS97 program. The positions of all the non-hydro-
gen atoms were included in the full-matrix least-squares refinement
yellow blocks which are suitable for X-ray diffraction, m.p. 145–
1
13
1
47 °C. H NMR (400 MHz, CDCl ) δ: 1.22 (t, J = 7.4 Hz, 3H, CH ),
using SHELXL97 program. H atoms were added at calculated posi-
3
3
2
.80 (m, 2H, CH ), 7.37–7.55 (m, 8H, Ph), 7.72 (d, J = 7.8 Hz, 2H,
tions and refined using a riding model. H atoms were 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 set to 0.93 Å for phenyl H atoms, 0.97
Å for methylene H atoms and 0.96 Å for methyl H atoms, while N-H
distances were set to 0.86 Å. The software used to prepare molecular
2
−
1
Ph), 8.22 (br, 1H, NH). IR (KBr, cm ) ν: 3323, 3261, 1651, 1469,
+
1
410, 1338, 1146, 1088, 1004. MS (EI): m/z: 293 [M+H] . Anal. Calcd
for C H N O: C, 69.85; H, 5.52; N, 19.17. Found: C, 69.71; H, 5.57;
N, 19.16%.
17
16
4
Crystal data of 3: A yellow block of dimensions 0.50 × 0.40 ×
3
0
.20 mm was used for data collection with a Bruker SMART CCD
14
graphics was ORTEP-3 for Windows. Full crystallographic details
have been deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC 913401.
Table 4 Crystal data and structure refinement
The authors are very grateful to the National Natural Science
Foundation of China (No. 20802069), the Natural Science
Foundation of Zhejiang Province (No. Y2090985) and the
new-shoot Talents Project of Zhejiang Province (No.
2012R403045) for financial support.
Chemical formula
17 16 4
C H N O
Colour/shape
Yellow/Block
292.34
298(2)
0.71073
monoclinic
Formula weight
Temperature, K
Wavelength, Å
Crystal system
Space group
Received 6 December 2012; accepted 4 February 2013
Paper 1201659 doi: 10.3184/174751913X13626783814049
Published online: 19 April 2013
1
P 2 /c
Unit cell dimensions
a = 14.588(5) Å
b = 16.450(6) Å
c = 14.431(5) Å
β = 115.234(4) °
3132.6(18)
References
1
2
3
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8
3
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0.081
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4
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8
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1.98–25.00
–17/10, –19/19, –10/17
15512/5504 (Rint = 0.0539)
Multi-scan
1
986, 51, 3043.
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0.0112(13)
9
0
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1.014
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2
R = 0.0582, wR = 0.1638
1
2
12 G.W. Rao, Y.M. Guo and W.X. Hu, Chem. Med. Chem., 2012, 7, 973.
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R = 0.0870, wR = 0.1820
Largest diff. peak and hole/e Å−
3
13 G.M. Sheldrick, Acta Cryst., 2008, A64, 112.
0.362, –0.274
1
4 L.J. Farrugia, J. Appl. Cryst., 1997, 30, 565.

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