Syntheses and crystal structures of two unsymmetrical 1,2,4, 5-tetrazine derivatives

Article abstract of DOI:10.1007/s10870-012-0287-8

Two unsymmetrical 1,2,4,5-tetrazine derivatives, (6-(3,5-dimethyl-1H- pyrazol-1-yl)-1,2,4,5-tetrazin-3-ylamino) methanol (C₉H ₁₃N₇O, 3) and 4-(6-(3,5-dimethyl-1H-pyrazol- 1-yl)-1,2,4,5-tetrazin-3-yl) morpholine (C₁₁H₁₅N ₇O, 4), were synthesized from 3,6-bis(3,5-dimethyl-1H-pyrazol-1- yl)-1,2,4,5-tetrazine and the corresponding aliphatic amine (2-aminoethanol and morpholine, respectively), there structureswere confirmed by single-crystalX-ray diffractionmethods. Both molecules have very similar bond length and angle patterns, The crystal structures show that compound 3 is stabilized by intermolecular O-H-N, N-H-O hydrogen bonds and p-p interactions, while compound 4 is stabilized by π- π interactions. The structure analyses establish that compound 3 belongs to the monoclinic system, space group P2(1)/c, with crystal data a = 6.979(2) A, b = 9.563(3) A, c = 16.542(5) A, V = 1084.4(5) A³, Z = 4, F(000) = 496, R₁ = 0.0488, wR₂ = 0.1063. Compound 4 belongs to the orthorhombic system, space group P2(1)2(1)2(1), with crystal data a = 6.544(14) A, b = 12.085(3) A, c = 15.753(4) A, V = 1245.7(5) A3, Z = 4, F(000) = 552, R₁ = 0.0403, wR₂ = 0.0913. Springer Science+Business Media, LLC 2012.

Full text of DOI:10.1007/s10870-012-0287-8

J Chem Crystallogr (2012) 42:600–605
DOI 10.1007/s10870-012-0287-8
ORIGINAL PAPER
Syntheses and Crystal Structures of Two Unsymmetrical 1,2,4,
5-tetrazine Derivatives
•
•
•
Feng Xu Zhen-zhen Yang Jun-rong Jiang
Zhong-lu Ke
Received: 23 December 2011 / Accepted: 7 February 2012 / Published online: 25 February 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Two unsymmetrical 1,2,4,5-tetrazine derivatives,
(6-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazin-3-ylami-
no)methanol (C9H13N7O, 3) and 4-(6-(3,5-dimethyl-1H-pyra-
zol-1-yl)-1,2,4,5-tetrazin-3-yl) morpholine (C11H15N7O, 4),
were synthesized from 3,6-bis(3,5-dimethyl-1H-pyrazol-1-
yl)-1,2,4,5-tetrazine and the corresponding aliphatic amine
(2-aminoethanol and morpholine, respectively), there struc-
tureswereconfirmedbysingle-crystalX-raydiffractionmeth-
ods. Both molecules have very similar bond length and angle
patterns, The crystal structures show that compound 3 is sta-
bilized by intermolecular O–H–N, N–H–O hydrogen bonds
and p–p interactions, while compound 4 is stabilized by p–p
interactions. The structure analyses establish that compound
3 belongs to the monoclinic system, space group P2(1)/c,
Over the past few years, both 1,2,4,5-tetrazines and their
derivatives have attracted much attention because they possess
a wide spectrum of biological activities, such as anticancer [1],
anti-inflammatory [2], antiviral [3] and insecticidal [4]. Some
1,2,4,5-tetrazines are being tested and clinically evaluated as
potential new drugs. For example N,N0-bis(2-methylphenyl)-
3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide
(ZJGDHu-1), wasreported tohaveastrongeffectagainstsev-
eral tumor cell lines [5]. Motivated by the afore-mentioned
findings, and as a continuation of our program in the field of
unsymmetrical 1,2,4,5-tetrazines [6, 7], two 3,6-unsymmet-
rical substituent-1,2,4,5-tetrazines (3 and 4) are synthesized
by the substitution reaction of 3,6-bis(3,5-dimethyl-1H-
pyrazol-1-yl)-1,2,4,5-tetrazine (2) and corresponding ali-
phatic amine in acetonitrile (Scheme 1), and their crystal
structures were determined by X-ray diffraction methods.
˚
with crystal data a = 6.979(2) A, b = 9.563(3) A, c =
˚
3
˚
˚
16.542(5) A, V = 1084.4(5) A , Z = 4, F(000) = 496,
R1 = 0.0488, wR2 = 0.1063. Compound 4 belongs to the
orthorhombic system, space group P2(1)2(1)2(1), with crys-
˚
tal data a = 6.544(14) A,b = 12.085(3) A,c = 15.753(4) A,
˚
˚
Experimental
3
V = 1245.7(5) A , Z = 4, F(000) = 552, R1 = 0.0403,
˚
wR2 = 0.0913.
3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,4-dihydro-
1,2,4,5-tetrazine (BDT) (1) [8]
Keywords 1,2,4,5-tetrazine ꢀ Syntheses ꢀ Crystal
structure ꢀ Unsymmetrical ꢀ X-ray diffraction
To a well stirred solution of triaminoguanidine nitrate
(33.4 g, 0.2 mol) in water (200 ml) was added dropwise
acetylacetone at 60 °C within about 30 min, then the reac-
tion mixture was warmed to 70 °C for 4 h. After cooling,
the product was filtered, washed by water (50 ml) and dried
to get the pale yellow powder (22.3 g, 83.0%).
Introduction
The 1,2,4,5-tetrazine ring is an important structural motif found
in many biologically and pharmaceutically active compounds.
3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine
(BT) (2) [8]
F. Xu (&) ꢀ Z. Yang ꢀ J. Jiang ꢀ Z. Ke
Department of Biological & Chemical Engineering, Taizhou
Vocational & Technical College, Taizhou 318000, People’s
Republic of China
To a stirred solution of BDT (23 g, 0.08 mol) in N-methyl
pyrrolidone (120 ml) and acetic acid solution (160 ml,
e-mail: xufeng901@126.com
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601
Scheme 1 Preparation of the
two target 3,6-unsymmetrical
1,2,4,5-tetrazines
w = 10%) was slowly added dropwise aqueous solution of
sodium nitrite (100 ml, w = 10%) at 20–30 °C. The reac-
tion mixture was kept at room temperature with continuous
stirring for 3 h, then filtered, washed by water (50 ml) and
dried to get the red powder (20.5 g, 94.9%).
structures were solved with SHELXS97 and refined with the
full-matrix least-squares procedure on F2 by SHELXL97 [9].
Scattering factors incorporated in SHELXL97 were used.
P
The function w(|Fo|2-|Fc|2)2 was minimized, with w-1
=
[r2(Fo)2?(AP)2?BP], where P = [Max(Fo2,0)?2Fc/3].The
final values of A and B are listed in Table 1 together with
relevant crystal data and refinement details. All non-hydro-
gen atoms were located in a difference Fourier map and
refined anisotropically. All hydrogen atoms located at geo-
metrically calculated positions and treated by a mixture of
independent and constrained refinement.
3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-alkylamino-1,2,4,
5-tetrazine (3 and 4)
To a solution of BT (2.7 g, 0.01 mol) in acetonitrile
(40 ml) was added dropwise corresponding alkylamine
(0.012 mol). The reaction mixture was heated to 40–50 °C
for 2–3 h with TLC monitoring (ethyl acetate:hexane =
7:3), which was then cooled on ice, the red solid was fil-
tered and recrystallized from methanol.
Results and Discussion
Compound 3: m.p. 153–155 °C. 1HNMR (400 MHz,
CDCl3) d: 2.36 (s, 3H), 2.56 (s, 3H), 3.84 (t, J = 5.0 Hz,
2H), 3.90 (t, J = 5.0 Hz, 2H), 6.12 (s, 1H). IR(KBr)
m cm-1, 3340, 3141, 1567, 2875, 1480, 1419, 1080, 1049,
962,789; Anal. Calcd for C11H15N7O: C, 45.95; H, 5.57; N,
41.68; O, 6.80; Found: C, 46.01; H, 5.60; N, 41.57; O, 6.72.
m/z = 236.1[M ? H]?.
Compound 4: m.p. 114–115 °C. 1HNMR (400 MHz,
CDCl3) d: 2.36 (s, 3H), 2.56 (s, 3H), 3.85 (t, J = 4.9 Hz,
4H), 4.01 (t, J = 4.9 Hz, 4H), 6.09 (s, 1H); IR(KBr)
m cm-1, 2990, 2918, 2858, 1572, 1484, 1450, 1396, 1305,
1262, 1083, 946; Anal. Calcd for C11H15N7O: C, 50.56; H,
5.79; N,37.53; O, 6.12; Found: C, 50.75; H, 5.92; N, 37.59;
O, 6.20. m/z = 262.1[M ? H]?.
1
The results of the HNMR, IR, MS and elemental analysis
are in agreement with the structures of the compounds 3
and 4. Figures 1, 2 show the perspective views of the
molecules 3 and 4, respectively, which were drawn with
the program ORTEP-3 [10]. Table 2 compares the geo-
metric parameters of both molecules. The bond lengths and
angles in both compounds are very similar, and even the
results of the normal probability plot set [11] confirm that
the differences between the molecules are mainly of sta-
tistical nature. Within the pyrazole ring of compound 3, the
˚
bond lengths of N(1)–C(2) [1.328(19) A] and C(3)–C(4)
˚
[1.370(2) A] are both longer than their typical values [1.29
˚
and 1.34 A, respectively [12]; the bonds C(2)–C(3)
˚
˚
[1.403(2) A], N(2)–C(4) [1.378(19) A] and N(1)–N(2)
˚
[1.381(16) A] are shorter than their typical values [1.47,
X-ray Crystallography
˚
1.43 and 1.45 A], respectively [12]. The bond lengths of
˚
the tetrazine ring C(6)–N(6) [1.324(19) A], N(5)–C(7)
X-ray quality crystals were obtained by slow evaporation of
ethyl acetate solution for compound 3 and 4. Diffraction
data were collected at 103 K by the w–x scans technique, on
a Rigaku AFC10 diffractometer with a Saturn724? CCD
detector using graphite-monochromated MoK a radiation
˚
[1.345(19) A], N(4)–C(7) [1.367(19) A] are shorter than
˚
˚
C–N single bonds [1.43 A], but longer than C=N double
˚
bonds [1.29 A]; similarly, N(5)–N(6) [1.334(18) A], N(3)–
˚
˚
N(4) [1.312(17) A] and N(3)–C(6) [1.343(19) A] are
˚
˚
shorter than N–N single bonds [1.45 A], but longer than
˚
from rotating anode graphite source (k = 0.71073 A).The
123

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J Chem Crystallogr (2012) 42:600–605
Table 1 Crystal data and
experimental crystallographic
details
Compound
3
4
Empirical formula
Formula weight
Temperature (K)
C9H13N7O
235.26
C11H15N7O
261.30
163 (2)
163 (2)
˚
Wavelength (A)
k = 0.71073
Monoclinic
P21/c
k = 0.71073
Orthorhombic
P212121
Crystal system
Space group
Cell dimensions
˚
a (A)
6.979 (2)
9.563 (3)
16.542 (5)
100.777 (4)
1084.4 (5)
4
6.5437 (14)
12.085 (3)
15.753 (4)
90.00 (2)
1245.7 (5)
4
˚
b (A)
˚
c (A)
b (°)
Volume (A )
3
˚
Z
Density(calculated) (Mg/m3)
Absorption coefficient (mm-1
F000
1.441
1.393
)
0.104
0.098
496
552
Crystal size (mm)
h range for data collection (o)
0.36 9 0.24 9 0.19
3.29–29.10
0.32 9 0.28 9 0.24
2.12–29.13
hkl range
-9BhB9, -12BkB13,
-20BlB22
-8BhB8, -16BkB14,
-20BlB21
Reflections collected
9262
10902
Unique (Rint
)
2893 (0.0349)
3304 (0.0344)
Weighting scheme
A
0.0359
0.5680
0.0435
0.1600
B
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I[2r(I)]
R indices (all data)
Full-matrix least-squares on F2
Full-matrix least-squares on F2
2893/0/164
3304/0/175
0.999
0.999
R1 = 0.0488, wR2 = 0.0966
R1 = 0.0726, wR2 = 0.1063
0.263/-0.248
R1 = 0.0403, wR2 = 0.0872
R1 = 0.0499, wR2 = 0.0913
0.236/-0.191
-3
)
˚
Largest diff. peak and hole (e A
CCDC deposit no.
819022
819023
The above results shows that the pyrazole ring, tetrazine
ring and atoms N(7) are conjugated system. A similar sit-
uation also occurs in compound 4.
As can be seen in Table 2, the internal and external
angles of the pyrazole ring in both of the two title com-
pounds follow the set of empirical rules given by Bonati
and Bovio [13], taking compound 3 for example, such that
(a) C(2)–N(1)–N(2) [104.52(12)o] is smaller than N(1)–
N(2)–C(4) [111.96(12)o]; (b) C(3)–C(2)–N(1) [111.28(13)o]
is larger than C(2)–N(1)–N(2) [104.52(12)o], C(2)–C(3)–
C(4) [106.97(13)o] and C(3)–C(4)–N(2) [105.27(13)o];
(c) C(2)–C(3)–C(4) is not the largest internal angle;
(d) N(1)–N(2)–C(6) [118.23(12)o] is smaller than C(4)–
N(2)–C(6) [129.78(13)o]; (e) N(1)–C(2)–C(1) [120.47(14)o]
is smaller than C(3)–C(2)–C(1) [128.24(14)o].
Fig. 1 Molecular structure of the compound 3. Displacement ellip-
soids shown at 30% probability
˚
N=N double bonds [1.25 A]. Furthermore, the bond lengths
˚
N(2)–C(6) [1.406(19) A] and N(7)–C(7) [1.340(2) A] in
˚
˚
Fig. 1 are both shorter than their typical values [1.43 A].
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J Chem Crystallogr (2012) 42:600–605
603
In compound 3, the pyrazole ring are almost coplanar
˚
within 0.001 A. The atoms N(3), N(4), N(5) and N(6) are
˚
almost coplanar within 0.002 A, while C(6),C(7) and N(7)
˚
deviate from the plane by 0.085, 0.117 and 0.306 A,
respectively. The plane N(3)/N(4)/N(5)/N(6) make a dihe-
dral angles of 6.92 (2) and 86.82 (2)o with the pyrazole ring
and C(8)/C(9)/O(1) chain, respectively. In compound 4, the
pyrazole ring, N(3)/N(4)/N(5)/N(6) and the C(8)/C(9)/C(10)/
C(11) planes are almost coplanar within 0.001, 0.002 and
˚
0.005 A, respectively. C(6) and C(7) deviate from the
˚
N(3)/N(4)/N(5)/N(6) plane by 0.074 and 0.094 A, respec-
Fig. 2 Molecular structure of the compound 4. Displacementellipsoids
shown at 30% probability
tively. N(7) and O(1) deviate from the plane C(8)/C(9)/
C(10)/C(11) by 0.673 and 0.588 in the opposite direction,
which causes the morpholine ring to exhibit a chair con-
formation. The plane N(3)/N(4)/N(5)/N(6) makes dihedral
o
Table 2 Selected bond distances (A) and angles ( ) of the compound
˚
3 and 4
3
4
N1–C2
1.328(19)
1.370(2)
1.321(18)
1.366(19)
1.414(2)
C3–C4
C2–C3
1.403(2)
N2–C4
1.378(19)
1.381(16)
1.328(19)
1.406(19)
1.324(19)
1.334(18)
1.345(19)
1.367(19)
1.312(17)
1.343(19)
1.340(2)
1.384(17)
1.383(16)
1.321(18)
1.407(16)
1.336(18)
1.322(16)
1.356(17)
1.361(18)
1.320(16)
1.334(17)
1.347(17)
1.470(17)
1.512(2)
N1–N2
N1–C2
N2–C6
C6–N6
N5–N6
N5–C7
N4–C7
N3–N4
Fig. 3 The hydrogen bonded chains of molecules 3 as seen along a
direction. Hydrogen bonds are shown as dashed lines
N3–C6
C7–N7
N7–C8
1.458(2)
˚
Table 3 Hydrogen-bonding geometry (A, °)
C8–C9
1.517(2)
˚
˚
˚
D–HꢀꢀꢀA
D–H (A) HꢀꢀꢀA (A) DꢀꢀꢀA (A) D–HꢀꢀꢀA (°)
O1–C9
1.423(18)
111.28(13)
106.97(13)
128.24(14)
120.47(14)
104.52(12)
105.27(13)
111.28(13)
129.78(13)
118.23(12)
111.96(12)
117.30(12)
116.79(12)
124.08(13)
117.25(12)
117.02(12)
119.65(14)
116.21(13)
1.424(19)
111.48(12)
106.77(12)
128.09(14)
120.43(13)
104.55(11)
105.28(12)
111.48(12)
129.94(12)
118.12(11)
111.92(11)
117.47(12)
117.15(12)
123.87(12)
117.41(12)
117.28(12)
118.46(12)
117.67(12)
N1–C2–C3
C2–C3–C4
C3–C2–C1
N1–C2–C1
C2–N1–N2
C3–C4–N2
C3–C2–N1
C4–N2–C6
N1–N2–C6
N1–N2–C4
C6–N6–N5
N6–N5–C7
N5–C7–N4
C7–N4–N3
N4–N3–C6
N5–C7–N7
N4–C7–N7
O1–H10ꢀꢀꢀN1i
0.85
2.14
2.47
1.99
2.984(2)
2.990(2)
2.861(4)
170
120
172
O1–H10ꢀꢀꢀN3i
0.85
N7–H7NꢀꢀꢀO1ii 0.88
Symmetry codes: (i) x, -1 ? y, z; 1 - z; (ii) 1 - x, 1/2 ? y, 1/2 - z
˚
Table 4 Intermolecular p–p interaction (A)
˚
Cg–Cg (A)
Cg–Cg
3
Cg1–Cg2i
Cg1–Cg2ii
4
Cg1–Cg2iii
Cg1–Cg2iv
3.574(12)
3.629(12)
3.517(12)
3.494(12)
Symmetry codes: (i) -x, 2-y, -z; (ii) 1-x, 2-y, -z; (iii) -1/2?x,
1/2-y, 1-z; (iv) 1/2?x, 1/2-y, 1-z. Cg1 is the centroid of the
pyrazole ring; Cg2 is centroid of the tetrazine ring
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J Chem Crystallogr (2012) 42:600–605
Fig. 4 The crystal packing of 3 viewed down the b axis. A portion of the intermolecular p–p interactions are shown as double headed arrows
Fig. 5 The crystal packing of 4 viewed down the b axis. A portion of the intermolecular p–p interactions are shown as double headed arrows
angle with the pyrazole ring, 4.72(2)o, while the twist with
respect to the plane C(8)/C(9)/C(10)/C(11) is 38.29(2)o.
In compound 3, intermolecular interactions involving
two directionally specific O–H–N and one N–H–O inter-
actions stabilize the packing along the b direction (Fig. 3;
Table 3), which forms twelve membered rings involving
three molecules and five membered rings involving two
molecules. In 4, no interesting intra- and inter-molecular
hydrogen bonding is seen within the molecule.
are different; the similar situation also occurred in com-
pound 4. In Fig. 5, the molecular layers are extended along
[001] direction, the adjacent three layers also show dif-
ferent centroid–centroid distances (Table 4).
Acknowledgments We are very grateful to the Foundation of
Taizhou Vocational and Technical College for support (grant No.
2012ZD05).
Intermolecular p–p interactions in 3 and 4 between
pyrazole rings and tetrazine rings are shown in Table 4. As
can be seen from Fig. 4, the crystal packing shows that the
molecular layers of 3 arranged along [10–1] direction. The
centroid–centroid distances among adjacent three layers
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