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

Article abstract of DOI:10.3184/174751912X13309508668509

1-(3-Methoxybenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine was prepared from 3-methoxybenzoyl chloride and 3,6-diphenyl-1,2(or 1,4)-dihydro-1,2,4,5-tetrazine, and its structure was determined by X-ray diffraction. This reaction yields the title compo

Full text of DOI:10.3184/174751912X13309508668509

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 197
APRIL, 197–199
Synthesis and structure analysis of 1-(3-methoxybenzoyl)-3,6-diphenyl-
1,4-dihydro-1,2,4,5-tetrazine
Guo-Wu Rao*, Yan-Mei Guo and Xiao-Min Li
College of Pharmaceutical Science, Zhejiang University ofTechnology, Hangzhou, 310014, P. R. China
1-(3-Methoxybenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine was prepared from 3-methoxybenzoyl chloride and
3,6-diphenyl-1,2(or 1,4)-dihydro-1,2,4,5-tetrazine, and its structure was determined by X-ray diffraction. This reaction
yields the title compound rather than 1-(3-methoxybenzoyl)-3,6-diphenyl-1,2-dihydro-1,2,4,5-tetrazine. The central
tetrazine ring of the title compound exhibits a boat conformation and therefore, is not homoaromatic.
Keywords: 1,2,4,5-tetrazine, X-ray diffraction, boat conformation
1,2,4,5-Tetrazine derivatives have high reactivities,1,2 good
potential for biological activities, and have been widely used
in organic synthetic chemistry and medicinal chemistry.3–6
Dihydro-1,2,4,5-tetrazine has four isomers, 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.7 There seems to be some doubt as to whether the
1,4-dihydro structures have homoaromaticity. For example,
X-ray diffraction reportedly showed 3,6-bis(4-chlorobenzyl)-
1,4-dihydro-1,2,4,5-tetrazine to have an obvious chair confor-
mation without a homoaromatic structure,8 but 1,3,4,6-tetra-
methyl-1,4-dihydro-1,2,4,5-tetrazine was analysed by X-ray
diffraction and a possible homoaromatic structure was identi-
fied.9 There seems to be much 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 scientists believe that rearrange-
ment can occur between 1,2- and 1,4-dihydro-1,2,4,5-tetrazine
isomers.10
studies failed to confirm whether the product has a homoaro-
matic structure 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.
The molecular structure of compound 3 is illustrated in
Fig. 1. Selected bond lengths are listed in Table 1. In the mol-
ecule (Fig. 1), the N2=C3 [1.283(2) Å] and N5=C6 [1.269(2)
Å] bonds correspond to typical double bonds of C=N, and the
C3–N4 [1.370(2) Å], N4–N5 [1.387(2) Å], C6–N1 [1.415(2)
Å] and N1–N2 [1.436(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-hydro-
gen at the 4 and not the 2-position, the compound being 1-(3-
methoxybenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine,
(3), rather than 1-(3-methoxybenzoyl)-3,6-diphenyl-1,2-dihy-
dro-1,2,4,5-tetrazine, (4).
In compound 3, atoms N2, C3, N5 and C6 are coplanar, with
the largest deviation from the plane (plane 1) being –0.0219
(8) Å for atom N5. The least-squares plane is listed in Table 2.
The adjacent N1 and N4 atoms deviate from plane 1 by 0.4291
(24) and 0.3403 (23) Å, respectively. The dihedral angle
between plane 1 and the N1/N2/C6 plane is 34.04 (13) °, and
between plane 1 and the N4/N5/C3 plane is 28.35 (13) °. The
difference in the dihedral angles is presumably due to a steric
effect of the substituent at the 1-position. The central tetrazine
ring of compound 3 exhibits an obvious boat conformation
(Fig. 2) and is therefore not homoaromatic. The dihedral angles
In a continuation of our studies of structure–activity rela-
tionships in 1,2,4,5-tetrazine derivatives,8,11,12 we have obtained
a yellow crystalline compound that was the product of the
reaction of 3-methoxybenzoyl chloride and 3,6-diphenyl-
1,2(or 1,4)-dihydro-1,2,4,5-tetrazine (compound 1 or 2). The
latter was prepared according to the literature procedure.8 As
Scheme 1 shows, there are two possible compounds, (3) and
(4), that could be the product. However, IR, NMR and MS
Scheme 1 Synthesis of 3.
* Correspondent. E-mail: rgw@zjut.edu.cn

198 JOURNAL OF CHEMICAL RESEARCH 2012
As shown in the packing of compound 3 (Fig. 3), there exists
one intramolecular hydrogen contact [C21–H21···N2] and
weak intermolecular N—H···O and C—H···O hydrogen bonds
(Table 3). Intramolecular and intermolecular interactions play
a major role in stabilising the molecules in the unit cell.
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.
1-(3-Methoxybenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (3):
3,6-Diphenyl-1,2(or 1,4)- dihydro-1,2,4,5-tetrazine (1.202g, 5.1 mmol),
prepared according to the procedure of Rao et al.8, and pyridine
(1 mL) were dissolved in dichloromethane (40 mL) with stirring. 3-
Methoxybenzoyl chloride (1.870 g, 11.0 mmol) and dichloromethane
(20 mL) were added dropwise into the mixture at room temperature
for 25 minutes. The mixture was stirred at room temperature for 10 h
and at 32˚C for 9h. Then the solvent was removed in vacuo and the
residue was washed with petroleum ether to afford the crude product.
The crude product was purified by flash column chromatography on
silica gel using petroleum ether/ethyl acetate (4:1, v/v) as eluent to
afford compound 3 (1.133 g, 60.1%) as a yellow solid. A solution
of the compound in ethanol was concentrated gradually at room
temperature to afford yellow blocks which are suitable for X-ray dif-
fraction, m.p. 162–164˚C. 1H NMR (500 MHz, CDCl3) δ: 3.84 (s, 3H,
CH3), 7.01 (d, J = 6.5 Hz, 1H, C6H4),7.32–7.72 (m, 13H, Ph and C6H4),
8.04 (s, H, NH). IR(KBr, cm−1) ν: 3444, 3313, 1635, 1617, 1463,
1392, 1096, 1037, 1014, 968. MS (EI): m/z: 370 [M]+. HRMS (EI):
m/z [M]+ Calcd for C22H18N4O2: 370.1430; found: 370.1426.
Fig.1 Themolecularstructureof3,shownwith30%probability
displacement ellipsoids.
Table 1 Selected bond lengths (Å)
Bond lengths
N1–N2
N2–C3
C3–N4
1.436(2)
1.283(2)
1.370(2)
N4–N5
N5–C6
N1–C6
1.387(2)
1.269(2)
1.415(2)
Table 2 Least-squares plane
Orthonormal
equation
of plane 1
8.8049 (31) x + 0.8076 (171) y – 6.4637 (82) z
= 7.3787 (162)
Atom
N2
C3
N5
C6
–0.0213 (8) 0.0217 (8) –0.0219 (8) 0.0214 (8)
Fig. 3 A portion of the crystal packing of 3. Hydrogen bonds
are shown as dashed lines. H atoms not involved in hydrogen
bonding were omitted for clarity.
Fig. 2 A boat conformation of compound 3, shown with 10%
probability displacement ellipsoids.
Table 3 Hydrogen-bond geometry bond lengths(Å) and angles(°)
Donor–H···Acceptor
D–H
H···A
D···A
D–H···A
between plane 1 and the three phenyl rings of the C1/C2/C4/
C5/C7/C8, C9/C10/C11/C12/C13/C14 and C16/C17/C18/
C19/C20/C21 plane are 29.18 (8), 30.67 (10) and 69.24 (9) °,
respectively. The dihedral angle between the two phenyl rings
of 3,6-positions is 59.10 (6) °.
N4–H4···O1i
C8–H8···O1i
C21–H21···N2
0.86
0.93
0.93
2.55
2.49
2.40
2.970(2)
3.376(2)
2.867(2)
111.1
159.9
110.7
Symmetry code: (i) 2–x, y–1/2, 1/2–z.

JOURNAL OF CHEMICAL RESEARCH 2012 199
Crystal data of 3: A yellow block of dimensions 0.50 × 0.47 ×
0.32 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 imple-
mented in SHELXS9713 program. The positions of all the non-hydro-
gen atoms were included in the full-matrix least-squares refinement
using SHELXL9714 program. H atoms were added at calculated posi-
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, and
0.96 Å for methyl 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 861589. 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).
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 13 January 2012; accepted 15 February 2012
Paper 1201105 doi: 10.3184/174751912X13309508668509
Published online: 17 April 2012
Table 4 Crystal data and structure refinement
Chemical formula
C22H18N4O2
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Largest diff. peak and hole (e Å−3) 0.265, –0.195

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