Preparation, mechanism, and supramolecular structure study of a novel benzimidazole-hydrate

Article abstract of DOI:10.1007/s10870-010-9694-x

A novel bis[2-(2-chloro-4-fluorophenyl)-1HBenzimidazole]- hydrate was prepared from Schiff base, and its single crystalline was obtained. The single crystalline was characterized by X-ray crystallography, and the results shows that the title complex belongs to the triclinic system, space group (P1) with lattice parameters a = 7.592 (2) A , b = 7.595(2) A , c = 11.886 (3) A , V = 574(3) A ³, Mr = 352.33, Dc = 1.478 g/cm ³, μ(MoKα) = 0.33 mm-1, F(000) = 262, Z = 1, the final R = 0.090 and wR = 0.209 for 2,315 observed reflections (I>2σ(I)). The crystal structure is formed by two benzimidazole molecules which are linked by a water molecule. A UV-Vis spectrophotometer and a fluorophotometer were used to detect the benzimizadole-hydrate crystal transformation process, which shows that benzimidazole-hydrate can only be formed from Schiff base effectively when ortho-hydroxyl group does not exist in benzaldehyde. The synthesis mechanism was also discussed. Compared with its Schiff base, benzimidazole-hydrate displays stronger fluorescence. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s10870-010-9694-x

J Chem Crystallogr (2010) 40:546–550
DOI 10.1007/s10870-010-9694-x
ORIGINAL PAPER
Preparation, Mechanism, and Supramolecular Structure Study
of a Novel Benzimidazole-Hydrate
•
Yong Hong Jing-Yi Xiao Ke-Long Huang
•
•
•
Jin-Gang Yu Du-Shu Huang
Received: 18 February 2009 / Accepted: 7 January 2010 / Published online: 7 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A novel bis[2-(2-chloro-4-fluorophenyl)-1H-
Benzimidazole]-hydrate was prepared from Schiff base,
and its single crystalline was obtained. The single crys-
talline was characterized by X-ray crystallography, and the
results shows that the title complex belongs to the triclinic
Introduction
Benzimidazole and its derivatives are important bioactive
molecules in pharmaceutical fields [1]. Not only can they be
used for producing medicines such as Omeprazole and
Pimobendan, but also have they exhibited significant activ-
ities against some viruses including RSV [2], herpes (HCV)
[3], HIV [4] and human cytomegalovirus (HCMV) [5].
Preparation of 2-substituted benzimidazoles from phenylene
diamines and carboxylic acids or carboxylic acid derivatives
was usually carried out under rigorous dehydrating condi-
tions [4], and addition of Lewis acids [5], inorganic clays [6],
mineral acids [7], or PyBOP [8] could improve their yields
and purity. However, toxic or environment-hazardous
byproducts will be produced under most of these procedures.
Moreover, these procedures are time-consuming, labour-
consuming and/or low output. A two-step procedure that
includes oxidative cyclodehydrogenation of aniline Schiff
bases has also been reported [9, 10], which is an in situ
condensation reaction of phenylenediamines and aldehydes.
However, special oxidants are urgently needed.
system, space group (P1) with lattice parameters a = 7.592
3
(2) A, b = 7.595(2) A, c = 11.886 (3) A, V = 574(3) A ,
˚
˚
˚
˚
Mr = 352.33, Dc = 1.478 g/cm3, l(MoKa) = 0.33 mm-1
,
F(000) = 262, Z = 1, the final R = 0.090 and wR = 0.209
for 2,315 observed reflections (I [ 2r(I)). The crystal
structure is formed by two benzimidazole molecules which
are linked by a water molecule. A UV–Vis spectropho-
tometer and a fluorophotometer were used to detect
the benzimizadole-hydrate crystal transformation process,
which shows that benzimidazole-hydrate can only be
formed from Schiff base effectively when ortho-hydroxyl
group does not exist in benzaldehyde. The synthesis
mechanism was also discussed. Compared with its
Schiff base, benzimidazole-hydrate displays stronger
fluorescence.
Keywords Benzimidazole Á Schiff base Á Crystal
In this work, we demonstrated that benzimidazole
derivatives could be prepared from Schiff base compounds
directly. The mechanism of the reaction was also discussed.
structure Á UV–Vis spectrophotometer Á Fluorophotometer
Experimental
Synthesis of Bis[2-(2-Chloro-4-Fluorophenyl)-
1H-Benzimidazole]-Hydrate
Y. Hong Á J.-Y. Xiao Á K.-L. Huang (&) Á J.-G. Yu Á
D.-S. Huang
College of Chemistry and Chemical Engineering,
Central South University, 410083, Changsha,
Hunan, China
A mixture of o-phenylenediamine (108 mg, 1 mmol),
2-chloro-4-fluorobenzaldehyde (317 mg, 2 mmol) and
ethanol (5 mL) was stirred in an ice bath for 1 h to prepare
Schiff base (3.8 g, yield 85%). The Schiff base (3.45 g,
e-mail: klhuang@mail.csu.edu.cn
J.-G. Yu
e-mail: yujg_zhoufl@yahoo.com
123

J Chem Crystallogr (2010) 40:546–550
547
˚
Table 1 Crystal data and structure refinement
Table 2 Hydrogen-bond geometry (A, °)
Compound
II
D–H_A
D–H
H_A
D_A
D–H_A
Empirical formula
Formula weight
Crystal size (mm)
Crystal system
Space group
C26H18Cl2F2N4O
511.34
O1W–H1WA_N1
O1W–H1WB_N4
N2–H2B_O1W(i)
N3–H3A_O1W(ii)
0.85
0.85
0.86
0.86
1.96
2.20
2.03
2.09
2.791(8)
2.811(8)
2.876(8)
2.904(8)
165
129
168
158
0.19 9 0.07 9 0.05
Triclinic
P1
Symmetry codes: (i) x - 1, y, z; (ii) x, y ? 1, z
˚
a (A)
7.569(2)
7.595(2)
11.886
˚
b (A)
for X-ray measurements, and data collection was carried
out on a CCD area detector diffractometer (Mo Ka,
k = 0.07107 nm) at 273 K. The data were corrected for
absorption empirically by the psi-scan method. The struc-
ture was solved by direct and difference Fourier methods
and refined by full-matrix least-squares on F2. All non-H
atoms were refined with anisotropic displacement param-
eters. All H atoms were generated automatically except for
the H atoms of water which generated manually, that is,
generated theoretically. The crystallographic computing
was performed using SHELXL97 [11]. The crystal
parameters, data collection and refinement results for the
compound are listed in Table 1. Selected bond lengths and
angles are listed in Table 2.
˚
c (A)
a (°)
b (°)
c (°)
82.559
73.479
61.286
˚
V (A)
574.5(3)
1
Z
Dc (g cm-3
)
1.478
l (mm-1
)
0.33
F(000)
262
Index ranges
-9 2 h 2 9
-9 2 k 2 9
-9 2 l 2 14
2,315
Reflns measured
R int
0.025
S on F2
1.08
R1, WR2 (I [ 2)
R1, WR2 (all data)
0.070, 0.167
0.090, 0.209
Results and Discussion
Structure Properties
yield 90%) was purified using ethyl acetate. The benzi-
mizadole-hydrate single crystalline suitable for X-ray
measurements were obtained using a mixed solution of
ethyl acetate and water.
The structure of compound II (Scheme 1) is shown in
Fig. 1. The water molecules participate in the hydrogen
bonds with the azido nitrogen molecules are shown in
Table 2, the bond lengths and bond angles are shown in
Table 3. In all essential details, the geometrical parameters
of the molecules in terms of bond lengths and angles show
general values. The bond lengths of C–C and C–N are
similar to those in 2-(2-ethoxyphenyl)-1-ethyl-1H-
Crystallography Measurements
A benzimizadole-hydrate single crystal sample with
dimensions of 0.19 mm 9 0.07 mm 9 0.05 mm was used
Scheme 1 Mechanism of
synthesis benzimidazole
F
Cl
CH
CH
N
N
NH
NH
2
N
N
F
Cl
Cl
Cl
F
+
2
CHO
F
II
I
F
HO
CH
NH
N
N
F
2
N
OH
CHO
O
H
F
+
H
CH
N
NH
2
O
F
123

548
J Chem Crystallogr (2010) 40:546–550
˚
Table 3 Selected bond lengths (A) and angles (°)
F1–C3
1.369(11)
1.325(11)
1.741(8)
1.758(8)
1.360(12)
1.391(11)
1.344(14)
1.328(16)
1.403(14)
1.399(10)
1.426(12)
1.344(10)
1.416(10)
1.362(10)
1.403(10)
1.417(11)
1.361(14)
1.399(13)
1.335(14)
121.1(8)
118.4(7)
120.5(6)
119.9(9)
122.6(9)
118.3(9)
119.1(10)
119.2(9)
120.0(9)
117.3(8)
124.4(7)
118.2(8)
109.0(7)
125.2(6)
125.5(6)
110.0(6)
132.2(7)
117.8(7)
119.6(8)
120.3(9)
123.4(9)
116.7(8)
106.3(6)
131.4(7)
122.2(7)
123.6(7)
115.7(6)
C12–C13
1.420(12)
1.350(11)
1.367(13)
1.392(11)
1.410(14)
1.358(15)
1.397(14)
1.379(11)
1.485(12)
1.292(10)
1.341(10)
1.357(10)
1.383(11)
1.423(11)
1.411(14)
1.362(15)
1.401(15)
1.348(12)
1.409(11)
F2–C16
C13–N2
Cl1–C1
C14–C15
Cl2–C14
C14–C19
C1–C2
C15–C16
C1–C6
C16–C17
C2–C3
C17–C18
C3–C4
C18–C19
C4–C5
C19–C20
C5–C6
C20–N4
C6–C7
C20–N3
C7–N1
C21–N3
C7–N2
C21–C22
Fig. 1 Perspective drawing of the title complex bis[2-(2-chloro-4-
fluorophenyl)-1H-Benzimidazole]-hydrate with the atomic number-
ing. Displacement ellipsoids are shown at the 30% probability level
C8–N1
C21–C26
C8–C13
C22–C23
C8–C9
C23–C24
C9–C10
C24–C25
benzimidazole [12] and 2-(2,4-dichlorophenyl)-1H-benz-
imidazole [13]. For compound II, the benzimidazole ring is
a plane with a torsional angle of C7–N1–C8–C9 being
179.96° and a dihedral angle being 40.697° between the
benzimidazole ring and benzene ring.
C10–C11
C11–C12
C2–C1–C6
C2–C1–Cl1
C6–C1–Cl1
C3–C2–C1
C4–C3–C2
C4–C3–F1
C2–C3–F1
C3–C4–C5
C6–C5–C4
C1–C6–C5
C1–C6–C7
C5–C6–C7
N1–C7–N2
N1–C7–C6
N2–C7–C6
N1–C8–C13
N1–C8–C9
C13–C8–C9
C10–C9–C8
C9–C10–C11
C12–C11–C10
C11–C12–C13
N2–C13–C8
N2–C13–C12
C8–C13–C12
C15–C14–C19
C15–C14–Cl2
C25–C26
C26–N4
C19–C14–Cl2
C14–C15–C16
F2–C16–C17
F2–C16–C15
C17–C16–C15
C16–C17–C18
C19–C18–C17
C18–C19–C14
C18–C19–C20
C14–C19–C20
N4–C20–N3
N4–C20–C19
N3–C20–C19
N3–C21–C22
N3–C21–C26
C22–C21–C26
C21–C22–C23
C24–C23–C22
C23–C24–C25
C26–C25–C24
C25–C26–N4
C25–C26–C21
N4–C26–C21
C7–N1–C8
C13–N2–C7
C20–N3–C21
C20–N4–C26
120.6(6)
116.9(9)
120.9(9)
117.4(10)
121.8(9)
119.1(8)
121.4(9)
117.2(8)
118.1(8)
124.8(7)
113.4(7)
121.1(6)
125.4(7)
132.5(8)
105.9(7)
121.7(8)
116.3(9)
121.6(10)
121.5(10)
118.4(9)
132.6(8)
120.4(8)
106.8(7)
106.9(6)
107.7(6)
107.9(6)
106.1(6)
It is very interesting that the crystal structure is formed
by two benzimidazole molecules, which were linked by a
H2O molecule as center. The structure is similar to the
complex of benzimidazole and can increase the stability of
the molecule. The angle of N1–O1–N4 is 117.89°. The
angle of the plane between phenyls of the benzimidazole
derivative molecules is 43.588°.
As shown in Fig. 2 and Table 2, two molecules of
compound II are linked by O1W–H1WÁN(1,2,3,4) inter-
molecular hydrogen bonds along a axis and b axis (sym-
metry code as in Table 2) and a two dimensional plane is
formed. The packing of compound I (Fig. 2) viewed along
c axis shows that one layer of molecules is connected by
O1W–H1WÁN hydrogen bonds (dashed lines). Both
hydrogen bonds and p–p stacking interactions between the
adjacent molecules devote to the three-dimensional net-
work. Therefore, both of them play a critical role to the
stability of the crystal lattice.
Spectral Analysis
Absorption and fluorescence spectra were measured using a
UV–Vis spectrophotometer (Unico 7200) and a fluoro-
photometer (Hitachi F-2500), respectively.
Chen et al. [14] have developed a fluorescence spec-
troscopic system for detecting the conversion procedure of
phenolic Schiff base to benzoxazoles. Herein, the rela-
tionship between the molecules and spectral changes was
discussed, and the reaction process was monitored using
UV–Vis and fluorescence spectroscopy.
The formation of benzimizole can be confirmed by
comparing the spectrum of compound I and compound II
(Fig. 3). The first peak can be assigned to the p ? p*
123

J Chem Crystallogr (2010) 40:546–550
549
3000
2500
2000
1500
1000
500
0
350
400
450
500
550
Fig. 4
benzimidazole
Fluorescence intensity changes of Schiff base and
Fig. 2 The packing of (I), viewed down the a axis, shows one layer
of molecules connected by O1W–H1W_N hydrogen bonds (dashed
lines). H atoms which don’t devote to form hydrogen bonds have been
omitted
Mechanism of the Reaction
The reaction can usually be carried out effectively in var-
ious solvents such as DMF and alcohol. The reaction rate
can be greatly enhanced in the presence of mineral acids.
We have also found a not complex procedure for the for-
mation of benzimidazoles by reaction of phenylenediam-
ines with benzaldehyde. It can greatly reduce reaction time
and enhance yields. Over 85% yields were obtained in our
experiments.
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
-0.2
However, if there were a hydroxyl group in the ortho-
position of the benzaldehyde, the reaction will be difficult
to occur. When 2-hydroxy-4-fluorobenzaldehyde was used
to synthesis benzimidazole, it was found that the reaction
could hardly be carried out under the same condition,
which showed that the conversion of benzimidazole from
Schiff base could only be carried out effectively when
200
300
400
500
600
Fig. 3 Absorption changes of Schiff base and benzimidazole
transition due to the imine nitrogen atoms in conjugation
with phenyl group. The compound II showes a decreased
absorption peak at 272 nm (e = 0.85 9 104), and a new
increased absorption peak at 299 nm (e = 0.92 9 104) can
be attributed to the benzimidazole.
2.5
2.0
C
B
1.5
The fluorescence properties of the Schiff base and
benzimidazole were investigated at room temperature in
solid state (Fig. 4). No fluorescence emission can be
detected from the Schiff base. However, benzimidazole-
hydrate showes a high fluorescence peak. Due to presence
of the lone pair electrons of the donor atoms in the Schiff
base, whose fluorescence is probably quenched by the
occurrence of a photoinduced electron transfer (PET)
process. Because two benzimidazoles are linked by a
O1W–H1WÁN(1,2,3,4) intermolecular hydrogen bonds and
a perfect plane is formed, the so obtained benzimidazole-
hydrate shows excellent fluorescence properties.
1.0
A
0.5
0.0
200
300
400
500
600
Fig. 5 Absorption changes of compound a (A untreated; B with
NaOH addition; C with NaOH addition and heating up)
123

550
J Chem Crystallogr (2010) 40:546–550
Scheme 2 Synthesis of
benzimidazole from
compound (a)
o-hydroxyl does not exist in the benzimizadole. However,
the reaction can be carried out by heating in presence of
NaOH, which may be useful for synthesizing benzimid-
azole derivatives.
geometric structure and spectroscopic properties were
investigated by X-ray crystallography, UV–Vis spectro-
photometer and fluorophotometer. The reaction mechanism
was also proposed.
A plausible pathway for preparation of benzimidazole
by an intra-molecular participation of imine of the inter-
mediate Schiff base to form the cyclic adduct was pro-
posed. The existence of o-hydroxyl leads to the formation
of hydrogen-bonds between the nitrogen atom and oxygen
atom, and the cyclization was blocked (Scheme 1).
The reaction was carried out under different conditions
to prove the possibility and reliability of the synthesis
procedure. The absorption changes of compound (a) in
ethanol with addition of NaOH are presented in Fig. 5. A
decreased adsorption at 342 nm and two new concomitant
increased absorptions at 400 nm corresponding to com-
pound (b) are from –OH deprotonation, which are similar
to the reported results [14]. However, no change can be
found at 254 nm. Due to the weaker electronegative
properties, the intra-molecular carbon–nitrogen bond of
benzimidazole is harder to form than the carbon–oxygen
bond of benzoxazolebut the reaction mechanism is very
similar. By heating up, the absorption band at 400 nm
decreases along with the increase of new absorption band
at about 290 nm, as shown in Fig. 5. The reaction may
undergo the pathway as shown in Scheme 2.
Acknowledgments Financial support from the National Natural
Science Foundation of China (No. 50772133) is greatly appreciated.
References
1. Valdez J, Cedillo R, Hernandez-Campos A et al (2002) Bioorg
Med Chem Lett 12:2221–2224
2. Wang XA, Cianci CW, Yu KL et al (2007) Bioorg Med Chem
Lett 17:4592–4598
3. Ishida T, Suzuki T, Hirashima S et al (2006) Bioorg Med Chem
Lett 16:1859–1863
4. Roth M, Morningstar ML, Boyer PL, Hughes SH, Bukheit RW,
Michejda CJJ (1997) Med Chem 40:4199–4207
5. Tandon VK, Kumar M (2004) Tetrahedron Lett 45:4185–4187
6. Bougrin K, Loupy A, Petit A, Daou B, Soufiaoui M (2001)
Tetrahedron 57:163–168
7. Rastogi R, Sharma S (1983) Synthesis 1983:861–882
8. Clemens JJ, Davis MD, Lynch KR, Macdonald TL (2004) Bioorg
Med Chem Lett 14:4903–4906
9. Austen SC, Kane JM (2001) J Heterocycl Chem 38:979–980
10. Lin S, Yang L (2005) Tetrahedron Lett 46:4315–4319
11. Sheldrick GM (1997) ShELXL-97, program for x-ray crystal
¨
structure determination. Gottingen University, Germany
12. Jian FF, Yu HQ, Qiao YB et al (2007) Acta Cryst E63:o321
13. Tong Y-P, Li W (2004) Acta Cryst E60:o1563
14. Chen Y, Xie NJ (2006) Photochem Photobiol A 179:320–323
Conclusions
A
2-(2-chloro-4-fluorophenyl)-1H-Benzimidazole was
synthesized by a convenient method from Schiff base. Its
123