Synthesis and Crystal Structures of Ethyl 2-(4-Methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate Dihydrate and Its Building Block 4-Fluoro-3-nitrobenzoic Acid

Article abstract of DOI:10.1007/s10870-018-0725-3

The title compound, ethyl 2-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate dihydrate (5), was synthesized and its crystal structure was studied by single-crystal X-ray diffraction technique. Compound 5 is crystallized in the centrosymmetric triclinic space group P1 ˉ with Z = 4 and Z′ = 2, and unit-cell parameters of a = 8.9190 (3) ?, b = 12.6888 (4) ?, c = 14.7111 (5) ?, α = 98.4855 (10)°, β = 101.6379 (9)°, γ = 95.4346 (10)° and V = 1599.43 (9) ?³. Its starting material, 4-fluoro-3-nitrobenzoic acid (1), is crystallized in the non-centrosymmetric monoclinic space group P2₁ and Z = 4 with unit-cell parameters of a = 3.7170 (4) ?, b = 12.6475 (13) ?, c = 15.5237 (15) ?, α = 90°, β = 91.9786 (16)°, γ = 90° and V = 729.35 (13) ?³. It was noted that strong hydrogen bonds play important roles in the crystal packing of both compounds, especially in 5, in which the co-crystallized water molecules act as both strong hydrogen bond donor and strong hydrogen bond acceptor. Graphical Abstract: Two molecule of compound 5 crystallized in a non symmetrical manner with four co-crystallized water molecules which play an important role in the crystal packing as strong hydrogen-bond donors. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10870-018-0725-3

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-018-0725-3
ORIGINAL PAPER
Synthesis and Crystal Structures of Ethyl 2-(4-Methoxyphenyl)-1H-
benzo[d]imidazole-5-carboxylate Dihydrate and Its Building Block
4-Fluoro-3-nitrobenzoic Acid
Keng Yoon Yeong1,2 · Tze Shyang Chia · Ching Kheng Quah · Soo Choon Tan
3
3
1
Received: 25 November 2015 / Accepted: 11 August 2018
©
Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The title compound, ethyl 2-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate dihydrate (5), was synthesized and its
crystal structure was studied by single-crystal X-ray diffraction technique. Compound 5 is crystallized in the centrosymmetric
̄
triclinic space group P1with Z=4 and Z′=2, and unit-cell parameters of a=8.9190 (3) Å, b=12.6888 (4) Å, c=14.7111 (5)
3
Å, α=98.4855 (10)°, β=101.6379 (9)°, γ=95.4346 (10)° and V=1599.43 (9) Å . Its starting material, 4-fluoro-3-nitroben-
zoic acid (1), is crystallized in the non-centrosymmetric monoclinic space group P2 and Z=4 with unit-cell parameters of
1
3
a=3.7170 (4) Å, b=12.6475 (13) Å, c=15.5237 (15) Å, α=90°, β=91.9786 (16)°, γ=90° and V=729.35 (13) Å . It was
noted that strong hydrogen bonds play important roles in the crystal packing of both compounds, especially in 5, in which
the co-crystallized water molecules act as both strong hydrogen bond donor and strong hydrogen bond acceptor.
Graphical Abstract
Two molecule of compound 5 crystallized in a non symmetrical manner with four co-crystallized water molecules which
play an important role in the crystal packing as strong hydrogen-bond donors.
Keywords Benzimidazole · Crystal structure · Hydrogen bonding · Cyclization
Introduction
4
-Fluoro-3-nitrobenzoic acid is a fundamental building
block for various pharmacologically important heterocy-
cles such as di- or tri-substituted benzimidazoles [1–3]. In
recent years, many medicinal chemistry research bearing
the benzimidazole scaffold related to cancer therapeutics
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10870-018-0725-3) contains
supplementary material, which is available to authorized users.
*
Keng Yoon Yeong
[
4], inflammation [5] and bacterial growth inhibition [6]
yeong.kengyoon@monash.edu
have been published. We have recently demonstrated the
Extended author information available on the last page of the article
Vol.:(0
1
123456789)
3

Journal of Chemical Crystallography
anticancer effect of novel substituted benzimidazole deriva-
electrospray ionization (ESI) mode. Crystal structure analy-
sis was carried out using a Bruker SMART APEX II DUO
CCD area-detector diffractometer.
tives based on the ethyl 2-phenyl-1H-benzo[d]imidazole-
5
-carboxylate scaffold through the inhibition of sirtuin activ-
ity [7]. Although the synthesis of the title compound, ethyl
-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate
2
Synthesis of Ethyl 2-(4-Methoxyphenyl)-1H-benzo[d]
imidazole-5-carboxylate Dihydrate (5)
dihydrate (5) has been previously published [8], no crystal
data was reported. Herein, we now would like to report the
first resolved crystal structure of 5 which was synthesized
using a different reaction route. The first crystal structure
of the starting material, 4-fluoro-3-nitrobenzoic acid (neat)
is also reported. The structure of the compounds was elu-
cidated using various techniques such as NMR, elemental
analysis, direct infusion-MS and unambiguously ascertained
through single-crystal X-ray crystallography.
The synthetic scheme of 5 utilized a facile and efficient
sequential one-pot protocol (Scheme 1) in mild reaction
conditions, similar to the published method in the previous
report [7]. One major advantage of this synthesis is that it
does not require any purification steps prior to obtaining the
final product 5. Apart from that, expensive catalysts were
also not needed during the course of the reaction making it
highly scalable. Briefly, 4-fluoro-3-nitrobenzoic acid 1, was
esterified in the presence of catalytic sulfuric acid in ethanol
by refluxing for 6 h to afford ethyl 4-fluoro-3-nitrobenzoate
Experimental
2
. Ammonium formate was subsequently added into the
solution, and the mixture stirred at room temperature for
.5 h. The resultant intermediate, ethyl 4-amino-3-nitroben-
Chemistry
0
All reagents were used as supplied without prior purifi-
cation. Melting points were determined on a Gallenkamp
MFB-595-010M melting point apparatus. Elemental
analyses were performed on a Perkin Elmer 2400 Series
zoate 3, was then reduced to ethyl 3,4-diaminobenzoate 4
using stannous chloride. Cyclization of intermediate 4 with
4-anisaldehyde and catalytic amounts of sodium metabi-
sulfite proceeded in a fast and smooth manner to afford final
compound 5 in good yield (90%). Recrystallization of crude
product 5 in ethyl acetate yielded light brown crystals, which
are suitable for X-ray crystallographic analysis. Melting
1
II CHN elemental analyzer. H NMR was performed on a
Bruker Avance 500 spectrometer in CDCl . Mass spectra
3
were recorded on a Varian 320-MS TQ LC/MS in positive
Scheme 1 Synthesis protocol of
O
O
benzimidazole derivative 5
HOOC
NO2
F
NO
2
EtOH
NH COOH
4
O
NO
F
2
O
EtOH
Reflux / 0.5 hr
NH
2
conc. H SO4
2
1
Reflux / 6 hrs
2
3
4-fluoro-3-nitrobenzoic acid
EtOH
Stannous chloride
Reflux / 0.5 hr
O
O
NH
2
2
NH
4
OCH
3
EtOH
Na
2
S
2
O
5
+
Reflux / 3 hrs
CHO
O
H
N
O
OCH
3
N
1
3

Journal of Chemical Crystallography
1
point: 188–189 °C. H NMR (300 MHz, CDCl ): δ 1.43 (3H,
SADABS programs [9]. The crystal structures were solved
by direct methods and refined by full-matrix least-squares
3
t, J=6.9 Hz), 3.88 (3H, s), 4.53 (2H, t, J=6.9 Hz), 7.06 (2H,
2
d, J=9 Hz), 7.47 (1H, d, J=9 Hz), 7.75 (2H, d, J=9 Hz),
techniques on F using SHELXTL package [11, 12]. The
1
3
8
.04 (1H, dd, J = 1.5 Hz, 9 Hz), 8.54 (1H, s). C NMR
carboxylic H atoms of 1 were located from difference Fou-
rier map, fixed at found positions (AFIX 3) and refined with
U (H)=1.5×U (O). The H atoms attached to water mol-
(
75 MHz, CDCl ): 14.69, 56.22, 61.45, 109.75, 109.98,
3
1
21.12, 122.18, 123.40, 150.05, 151.59, 168.67. ESI-MS:
iso
eq
+
m/z 297.1 [M+H] . Anal. Calc. for C H N O : C, 68.88;
ecules and benzimidazole N atom in 5 were located from
1
7
16
2
3
H, 5.50; N, 4.47%. Found: C, 68.90; H, 5.41; N, 4.50%.
difference Fourier map and refined freely [d(O–H) = 0.84
(
2)–0.95 (2) Å; d(N–H)=0.874 (19) and 0.92 (2) Å]. The
Single-Crystal X-Ray Structure Determination
C-bound H atoms were calculated geometrically and refined
with U (H)=1.2×U (C) for methine or methylene group,
iso
eq
X-ray data of 1 and 5 were collected by using Bruker
and U (H) = 1.5 × U (C) for methyl group. A rotating
iso eq
SMART APEX II DUO CCD area-detector diffractometer
group model (AFIX 137) was applied to the methyl group.
The crystal data, data collection and structure refinement
details of compounds 1 and 5 are tabulated in Table 1.
[
9] with Mo Kα radiation (λ=0.71073 Å). The sample tem-
perature was kept at 100 (1) K by using Oxford Cryosystems
Cobra open-flow nitrogen cryostat [10]. Data reduction and
absorption correction were performed by using SAINT and
Results and Discussion
The starting material, 4-fluoro-3-nitrobenzoic acid (1), is
a common fundamental building block for numerous het-
erocyclic compounds such as benzimidazoles and benzo-
diazenes. The single-crystals of 1 were successfully recrys-
tallized from isopropanol. Compound 1 is crystallized in
Table 1 Crystal and structure refinement data for compounds 1 and 5
1
5
CCDC deposition number 1437965
1437966
Chemical formula
Formula weight
Crystal system
Space group
a (Å)
b (Å)
c (Å)
α (°)
C H FNO
185.11
C H N O ·2(H O)
7
4
4
17 16
2
3
2
the non-centrosymmetric monoclinic space group P2 and
1
332.35
Triclinic
P1̄
Monoclinic
P21
3.7170 (4)
12.6475 (13)
15.5237 (15)
90
8.9190 (3)
12.6888 (4)
14.7111 (5)
98.4855 (10)
101.6379 (9)
95.4346 (10)
1599.43 (9)
4, 1.380
β (°)
γ (°)
91.9786 (16)
90
729.35 (13)
4, 1.686
0.16
3
Volume (Å )
Z, D (Mg m−3)
x
−
1
µ (mm
F(000)
Crystal size (mm )
θmax, θmin (°)
hkl range
)
0.10
704
Fig. 1 The ORTEP diagram of 1
376
3
0.28 × 0.15 × 0.08 0.33 × 0.24 × 0.13
28.2, 1.3
−4≤h≤4
28.2, 1.4
−11≤h≤11
−16≤k≤16
−19≤l≤19
49050
−
−
18113
3488
16≤k≤16
20≤l≤20
Measured reflections
Independent reflections
7833
Reflections with I>2σ(I) 2966
6577
0.030
Rint
0.049
Tmin, Tmax
0.673, 0.790
235/1
0.044
0.917, 0.960
477/0
0.041
Parameters/restraints
2
2
R[F >2σ(F )]
2
wR(F )
0.099
0.114
Fig. 2 The partial crystal packing of 1 shows two supramolecular
tapes with intermolecular hydrogen bonds (cyan lines) viewed along
a-axis. (Color figure online)
S
1.08
0.31, −0.33
1.04
0.34, −0.30
Δρmax, Δρmin (e Å−3
)
1
3

Journal of Chemical Crystallography
Z = 4. The asymmetric unit of 1 consists of two crystallo-
graphically independent acid molecules (A and B), which
are connected into a homodimer via strong intermolecular
O–H···O hydrogen bonds (Fig. 1). The meta-substituted
nitro groups are twisted away from the attached phe-
nyl rings with dihedral angles of 28.1 (3)° and 13.0 (4)°
for molecules A and B, respectively. In the crystal, acidic
homodimers are joined by weak intermolecular C–H···O
and C–H···F hydrogen bonds into infinite linear tapes along
crystallographic b-axis (Fig. 2). The crystal structure of 1 is
further stabilized by intermolecular π···π stacking interac-
tions (Fig. 3) along a-axis, involving the centroids of phenyl
rings between two molecules A and between two molecules
B with a centroid···centroid separation of 3.7170 (18) Å
Fig. 3 The intermolecular π···π interactions (magenta lines) of 1.
Color figure online)
(
(
symmetry codes: x−1, y, z; x+1, y, z). These π···π stack-
ing interactions of 1 involved parallel-displaced phenyl rings
with slippages of 1.417 and 1.466 Å. The multi-component
complexes of 1 with two active pharmaceutical ingredi-
ents, viz., caffeine and theophylline, were recently reported
[
13–15] and deposited in the Cambridge Structural Data-
base [16] with reference codes of ARIFUE, ZEKPIR and
ZEKPIR01. The characteristic carboxylic acid···carboxylic
acid homodimer of 1 is absent in the crystal structures of
these three complexes. Instead, the acid molecule forms
heterodimer with caffeine or theophylline molecule through
strong intermolecular O–H···N hydrogen bond between car-
boxyl and imidazole groups in the complexes. In addition,
in the crystals of ZEKPIR and ZEKPIR01, two adjacent
acid···theophylline heterodimers are interconnected by a pair
Fig. 4 The ORTEP diagram of the asymmetric unit of 5
Table 2 Hydrogen bond
D–H···A
D–H
H···A
D···A
D–H···A
Symmetry code
geometry (Å, °) (D: donor,
A: acceptor) for crystals of
compounds 1 and 5
1
O2A–H1O2···O1B
O2B–H2O2···O1A
C2A–H2AA···O3B
C6B–H6BA···F1B
5
0.95
0.84
0.95
0.95
1.68
1.79
2.59
2.46
2.609 (3)
2.625 (3)
3.290 (4)
3.266 (4)
168
173
131
143
x, y, z
x, y, z
x, y−1, z
−x−1, y−1/2, −z
N2A–H1N2···O1W
N2B–H2N2···O4W
O1W–H1W1···N1B
O1W–H2W1···O4W
O2W–H1W2···O3W
O2W–H2W2···O2A
O3W–H1W3···N1B
O3W–H2W3···O2B
O4W–H1W4···N1A
O4W–H2W4···O2W
C15A–H15A···O3W
C17A–H17C···Cg2
0.92 (2)
0.87 (2)
0.84 (2)
0.83 (3)
0.87 (3)
0.90 (2)
0.92 (2)
0.95 (2)
0.88 (2)
0.90 (2)
0.95
1.84 (2)
2.01 (2)
2.03 (2)
1.95 (3)
1.90 (3)
1.91 (2)
2.05 (2)
1.86 (2)
1.99 (2)
1.80 (2)
2.57
2.7357 (14)
2.8750 (15)
2.8613 (15)
2.7794 (15)
2.7647 (15)
2.8035 (13)
2.9586 (16)
2.7979 (14)
2.8622 (14)
2.6946 (14)
3.3419 (16)
3.5578(16)
164.1 (17)
173.4 (17)
174 (2)
174 (2)
174 (2)
174.5 (18)
168 (2)
169.7 (19)
171.4 (18)
176 (2)
138
−x+1, −y+1, −z+1
−x, −y+1, −z
x+1, y−1, z
x, y, z
x−1, y, z
−x+1, −y+1, −z+1
x+1, y−1, z
−x+1, −y+1, −z
x, y−1, z
x, y, z
x−1, y+1, z
−x, −y+2,−z+1
0.98
2.76
139
Cg2 is the centroid of C1A–C6A ring
1
3

Journal of Chemical Crystallography
Fig. 5 a The partial crystal
packing of 5 with co-crystal-
lized water molecules (red balls)
and hydrogen bonds (cyan lines)
viewed along c-axis. b The
water molecules of asymmetric
unit and their neighbouring
molecules in short contacts.
(
Color figure online)
of strong intermolecular N–H···O hydrogen bonds into an
acid···theophylline···theophylline···acid heterotetramer. The
N atoms of imidazole group of these two complexes act as
strong donor of N–H···O hydrogen bond and strong accep-
tor of O–H···N hydrogen bond as compared to ARIFUE, in
which the strong donating NH group is replace by a weak
(5)° and 0.23 (5)°. The terminal ethyl groups are twisted
away from the planar parent molecules with C8–O1–C9–C10
torsion angles of 160.99 (11)° and − 165.84 (12)°. All
water molecules in the crystal lattice are treated with full
occupancy since their U (O) values are in the range from
eq
2
0.0205 (2) to 0.0334 (3) Å . In the crystal of 5, molecules are
donating N–CH group.
joined by strong intermolecular N–H···O
, O
–H···N,
water
3
water
Compound 5 is crystallized in the centrosymmet-
O
–H···O and O
–H···O
hydrogen bonds into
water
water
water
̄
ric triclinic space group P1 with Z = 4 and Z′ = 2. The
two-dimensional networks parallel to crystallographic ac-
asymmetric unit of 5 (Fig. 4) consists of two major ethyl
plane (Fig. 5). The networks are further stabilized by weak
2
-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate
intermolecular C–H···O
, C–H···π (Table 2) and π···π
water
i
ii
molecules and four co-crystallized water molecules, which
play an important role in the crystal packing as strong hydro-
gen bond donors (Table 2). The molecular geometries of
both major molecules are similar after an inversion with a
RMSD of 0.0875 Å. The phenyl ring and benzimidazole ring
are almost co-planar as indicated by dihedral angles of 1.61
interactions (Cg1···Cg1 =3.5442 (7), Cg5···Cg6 =3.7277
iii
ii
(8), Cg5···Cg7 =3.6684 (8), Cg6···Cg5 =3.7276 (8) and
iii
Cg7···Cg5 =3.6684 (8) Å. Cg1, Cg5, Cg6 and Cg7 are the
centroids of N1A/C1A/C6A/N2A/C7A, N1B/C1B/C6B/N2B/
C7B, C1B–C6B and C11B–C16B rings, respectively. Sym-
metry codes: (i)−x+1, −y+2, −z+1; (ii)−x, −y+2, −z;
1
3

Journal of Chemical Crystallography
Fig. 6 The intermolecular
C–H···π and π···π interactions
(
magenta lines) of 5. (Color
figure online)
(
iii)−x −1, −y +2, −z). These π···π stacking interactions
Compliance with Ethical Standards
of 5 (Fig. 6) involved parallel-displaced phenyl rings with
Conflict of interest The authors hereby declare there is no conflict of
slippages of 0.647, 1.536, 1.235, 1.530 and 1.257 Å.
interests.
Conclusion
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Affiliations
Keng Yoon Yeong1,2 · Tze Shyang Chia · Ching Kheng Quah · Soo Choon Tan
3
3
1
1
3
Institute for Research in Molecular Medicine, Universiti
Sains Malaysia, 11800 USM, Penang, Malaysia
X-ray Crystallography Unit, School of Physics, Universiti
Sains Malaysia, 11800 USM, Penang, Malaysia
2
School of Science, Monash University Malaysia Campus,
4
7500 Bandar Sunway, Selangor, Malaysia
1
3