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

Article abstract of DOI:10.3184/174751912X13344174340577

1-(2-Chlorobenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine was prepared from 2-chlorobenzoyl 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 1,4-dihydro

Full text of DOI:10.3184/174751912X13344174340577

300 RESEARCH PAPER
MAY, 300–302
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis and structure analysis of 1-(2-chlorobenzoyl)-3,6-diphenyl-1,4-
dihydro-1,2,4,5-tetrazine
Guo-Wu Rao*, Li-Ling Zhang and Xiao-Min Li
College of Pharmaceutical Science, Zhejiang University ofTechnology, Hangzhou, 310014, P. R. China
1-(2-Chlorobenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine was prepared from 2-chlorobenzoyl 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 1,4-dihydro derivative rather than the 1,2-dihydro derivative. The central six-member ring of the title
compound exhibits a boat conformation and therefore, is not homoaromatic.
Keywords: tetrazine, X-ray diffraction, calculation, boat conformation
1,2,4,5-Tetrazine derivatives have good potential for biological
activities, and was widely used in organic medicinal chemistry
and synthetic chemistry.1–6 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.7 There
still seems to be some doubt as to whether the 1,4-dihydro
structures have homoaromaticity. For example, X-ray diffrac-
tion was reported to show 3,6-bis(4-chlorobenzyl)-1,4-dihy-
dro-1,2,4,5- tetrazine to have an obvious chair conformation
without homoaromatic structure,8 but 1,3,4,6-tetramethyl-1,4-
dihydro-1,2,4,5-tetrazine was analysed by X-ray diffraction
and a possible homoaromatic structure was identified.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, or the authors have formulated their compounds in
the dihydro structure which seemed to be the most accepted at
that time. Some scientists believe that rearrangement can occur
between 1,2- and 1,4-dihydro-1,2,4,5-tetrazine isomers.10
In continuation of our studies of antitumour activities 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 2-chlorobenzoyl 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 procedure of Rao et al.8 As
Scheme 1 shows, there are two possible compounds, (3) and
(4), for the product. However, IR, NMR and MS studies failed
to prove whether the product has a homoaromatic 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 molecule
(Fig. 1), the N2=C3 [1.284(2) Å] and N5=C6 [1.274(2) Å]
bonds correspond to typical double bonds of C=N, and the
C3–N4 [1.369(2) Å], N4–N5 [1.392(2) Å], C6–N1 [1.412(2)
Å] and N1–N2 [1.422(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-(2-
chlorobenzoyl)-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine,
(3), rather than 1-(2-chlorobenzoyl)-3,6-diphenyl-1,2-dihydro-
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 0.0202 (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 –0.4070
(24) and –0.3402 (27) Å, respectively. The dihedral angle
between plane 1 and the N1/N2/C6 plane is 32.88 (19)°, and
between plane 1 and the N4/N5/C3 plane is 28.45 (12)°. The
difference in the dihedral angles is presumably due to a steric
effect of the substituent at the 1-position. The central tetrazine
Scheme 1 Synthesis of 3.
* Correspondent. E-mail: rgw@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 301
Fig. 2 A boat conformation of compound 3, shown with 10%
probability displacement ellipsoids.
Table 2 Least-squares plane
Orthonormal
equation
of plane1
6.9222 (31) x –4.2038 (142) y + 0.7283 (196) z
Fig.1 Themolecularstructureof3,shownwith30%probability
displacement ellipsoids.
= 1.3865 (193)
Table 1 Selected bond lengths (Å)
Atom
N2
C3
N5
C6
0.0197 (8) –0.0201 (8) 0.0202 (8) –0.0198 (8)
Bond lengths
Orthonormal – 4.0098 (57) x + 9.5998 (73) y + 6.2816 (171) z
N2–C3
C3–N4
N1–N2
1.284(2)
1.369(2)
1.422(2)
N5–C6
C6–N1
N4–N5
1.274(2)
1.412(2)
1.392(2)
equation
= 7.2225 (108)
of plane 2
Atom
N1
O1
C15
C16
0.0044 (4) 0.0051 (5) –0.0135 (13) 0.0040 (4)
Fig. 3 A packing diagram of 3. Hydrogen bonds are shown as dashed lines. H atoms not involved in hydrogen bonding were
omitted for clarity.
Table 3 Hydrogen bond geometry (Å and °)
ring of compound 3 exhibits an obvious boat conformation
(Fig. 2) and therefore, is not homoaromatic. The dihedral
angles 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 17.88 (11), 31.08 (7) and 79.68
Donor–H···Acceptor
N4–H4···O1i
D–H
0.86
H···A
2.34
D···A
D–H···A
120
2.864(2)
Symmetry code: (i) 1/2+x, 1/2–y, –z.

302 JOURNAL OF CHEMICAL RESEARCH 2012
was solved by direct method procedures as implemented in
SHELXS9713 program. The positions of all the non-hydrogen atoms
were included in the full-matrix least-squares refinement using
SHELXL9714 program. H atoms were added at calculated positions
and refined using a riding model. H atoms were given isotropic
displacement parameters equal to 1.2 times the equivalent isotropic
displacement parameters of their parent atoms, and C–H distances
were set to 0.93 Å for phenyl H atoms, while N-H distances were set
to 0.86 Å. The final cycle of full-matrix least-squares refinement was
based on 3767 observed reflections (I > 2σ(I)) and 245 variable
parameters and converged with R = 0.0390 and wR = 0.1070. Full
crystallographic details have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number
CCDC 861590.
(7)°, respectively. The dihedral angle between the two phenyl
rings of 3,6-positions is 48.51 (7)°. Atoms N1, O1, C15 and
C16 are coplanar, with the largest deviation from the plane
(plane 2) being 0.0135 (13) Å for atom C15. The least-squares
plane is listed in Table 2. The phenyl ring of the C16/C17/C18/
C19/C20/C21 plane is 62.97(7)° angle to the N1/O1/C15/C16
plane. Thus it cannot be conjugated.
As shown in the packing of compound 3 (Fig. 3), there exists
weak intermolecular N—H···O hydrogen bond (Table 3).
Intermolecular interactions play a major role in stabilising the
molecules in the unit cell.
Experimental
Melting points were determined on an X-4 melting point apparatus
and are uncorrected. IR spectra were taken on a Thermo Nicolet
Avatar 370 FT-IR spectrophotometer (KBr pellets). H spectra
were recorded on a Bruker Avance III (500M) spectrometer. MS
spectra were obtained on a Thermo Scientific ITQ 1100TM mass
spectrometer.
The authors are grateful to the Natural Science Foundation of
Zhejiang Province (No. Y2090985) and the National Natural
Science Foundation of China (No. 20802069) for financial
support.
1-(2-Chlorobenzoyl)-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 (2.210g, 9.4 mmol),
prepared according to the procedure of Rao et al.8, and pyridine
(2 mL) were dissolved in dichloromethane (40 mL) with stirring.
2-Chlorobenzoyl chloride (3.500 g, 20.0 mmol) and dichloromethane
(40 mL) were added dropwise into the mixture at 5 °C. Then the mix-
ture was stirred at room temperature for 30 h. The solvent was removed
in vacuo and the residue was washed with petroleum ether (15 ×
5 mL) to afford the crude product. The crude product was purified
by flash column chromatography on silica gel using petroleum ether/
ethyl acetate (20:1, v/v) as eluent to afford compound 3 (0.639 g,
18.2%) as a yellow solid. A solution of the compound in ethanol was
concentrated gradually at room temperature to afford yellow blocks
Received 24 January 2012; accepted 13 March 2012
Paper 1201126 doi: 10.3184/174751912X13344174340577
Published online: 10 May 2012
References
1
S. Zhang, G.W. Rao, X.G. Mao and W.X. Hu, J. Chem. Res. 2011, 35,
275.
2
3
G.W. Rao, X.J. Lu and W.X. Hu, J. Chem. Res. 2010, 34, 301.
K. Lorincz, A. Kotschy, J. Tammiku-Taul, L. Sikk and P. Burk, J. Org.
Chem. 2010, 75, 6196.
4
5
6
7
H.S. Han, N. K Devaraj, J. Lee, S.A. Hilderbrand, R. Weissleder and
M.G. Bawendi, J. Am. Chem. Soc. 2010, 132, 7838.
N.K. Devaraj, R. Upadhyay, J.B. Haun, S.A. Hilderbrand and R. Weissleder,
Angew. Chem.Int. Ed. 2009, 48, 7013.
J. Sauer, Comprehensive heterocyclic chemistry, II, ed. A.J. Boulton,
Elsevier: Oxford, England, 1996, Vol. 6, pp. 901.
1
which are suitable for X-ray diffraction. M.p. 214–217 °C. H NMR
(500 MHz, CDCl3) δ: 7.382-7.493 (m, 12H, Ph and C6H4), 7.781 (s,
2H, Ph), 8.247(s, 1H, NH). IR(KBr, cm−1)ν: 3316, 1647, 1612, 1462,
1402, 1146, 1061, 961. MS (EI): m/z (%): 374 (1.94) [M]+. MS (ESI):
m/z: 375 [M+H]+, 397 [M+Na]+. HRMS (ESI): m/z [M+H]+ Calcd for
C21H16ClN4O: 375.1013; found: 375.1024.
3: C21H15ClN4O, Mr = 374.82, Orthorhombic, P 212121, a =
7.3706(10), b = 12.3065(18), c = 20.323(3) Å, V = 1843.4(5) Å3, Dx =
1.351 g cm−3, Z = 4, µ = 0.226 mm−1, T = 298 K. A yellow block
of dimensions 0.52 × 0.50 × 0.40 mm3 was used for data collection
with a Bruker Smart CCD area-detector diffractometer with graphite
monochromated Mo Kα radiation (λ = 0.71073 Å). The intensity data
were collected up to a θmax of 28.32° by the ω/2θ scan method. A total
of 11144 reflections were collected. The ranges of h, k, l are –9 h 5,
–15 k 15, –24 l 25. The intensities were corrected for Lorentz and
polarisation effects but not for absorption correction. The structure
C.P.R. Jennison, D. Mackay, K.N. Watson and N.J. Taylor, J. Org. Chem.,
1986, 51, 3034.
8
9
G.W. Rao and W.X. Hu, Bioorg. Med. Chem. Lett., 2006, 16, 3702.
G.W. Bemis, R.R. Whittle and S.L. Mayo, Acta Cryst. 1984, C40, 2076.
10 H. Neunhoeffer, Comprehensive heterocyclic chemistry, I, ed. A.R.
Katritzky, Pergamon: Frankfurt, 1984, Vol. 3, pp. 531.
11 G.W. Rao and W.X. Hu, Bioorg. Med. Chem. Lett., 2005, 15, 3174.
12 W.X. Hu, G.W. Rao and Y.Q. Sun, Bioorg. Med. Chem. Lett., 2004, 14,
1177.
13 G.M. Sheldrick, SHELXS-97. Program for the Solution of Crystal
Structures. University of Göttingen, Germany, 1997.
14 G.M. Sheldrick, SHELXL-97. Program for the Refinement of Crystal
Structures. University of Göttingen, Germany, 1997.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.