Synthesis, spectroscopic and structural studies of N-(1H-benzimidazol-2-yl) -N-benzyl propionamidine

Article abstract of DOI:10.1007/s10870-005-9006-z

N-(1H-Benzimidazol-2-yl) propionimidic acid ethyl ester (1) reacts with benzylamine to yield the corresponding N-(1H-Benzimidazol-2-yl)-N-benzyl proponamidine (2). The structure and conformation of the amidine 2 were determined by ¹H and ¹

Full text of DOI:10.1007/s10870-005-9006-z

ꢀ
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Journal of Chemical Crystallography, Vol. 37, No. 6, June 2007 ( 2007)
DOI: 10.1007/s10870-005-9006-z
Synthesis, spectroscopic and structural studies of
N-(1H-benzimidazol-2-yl)-Nꢀ-benzyl propionamidine
N. Raouafi,(1)∗ M. Freytag,(2) P.G. Jones,(2) and M.L. BenKhoud(1)
Received April 1, 2005; accepted June 10, 2005
Published Online March 24, 2007
N-(1H-Benzimidazol-2-yl) propionimidic acid ethyl ester (1) reacts with benzylamine
to yield the corresponding N-(1H-Benzimidazol-2-yl)-Nꢁ-benzyl proponamidine (2). The
1
structure and conformation of the amidine 2 were determined by H and 13C NMR and
X-ray diffraction. The product crystallizes in monoclinic system with space group P21/c,
◦
˚
˚
˚
a = 10.7913 A, b = 15.5164 A, c = 9.1130 A, β = 108.378 and Z = 4. In the crystal there
are two N–H· · ·N hydrogen bonds, the first is intramolecular H-Bond links H4 to N1; the
second one is intermolecular and it links H2 to N3 of a second molecule leading to inversion-
related dimers. The X-ray results were compared with those obtained by semi-empirical
and ab-initio calculations.
KEY WORDS: N-(1H-Benzimidazol-2-yl)-Nꢁ-benzyl propionamidine.; imidate; X-ray structure determination;
conformation; geometry optimization; quantum calculations.
Introduction
In order to establish the conformation of the
N-benzimidazol-2-yl Nꢁ-benzylamidine and better
The amidine functionality has been found to
understand its reactivity, an X-ray crystal structure
determination was carried out and the results have
been compared with those obtained from theoret-
ical calculations.
be critical in biological processes1,2 and is present
in many natural products.3,4 Also, amidines are
versatile synthetic intermediates for heterocyclic
synthesis due to the presence of two nucle-
ophilic centers.5 In addition, when amidine com-
pounds have another functional group containing
one or two nucleophilic centers, these sub-
strates may undergo cyclization reactions if they
are allowed to react with suitable electrophilic
compounds.6–8
Experimental
Synthesis of imidate 1 and amidine 2
Synthesis of N-benzimidazol-2-yl imidate 1.
The substrate 1 was synthesized, according to a
procedure described in the literature,9 by refluxing
2-aminobenzimidazole with a little excess of tri-
ethylorthopropionate in the presence of a catalytic
amount of acetic acid (Scheme 1).
(1)
Laboratoire de Chimie Analytique et Electrochimie, Faculte´ des
Sciences de Tunis, Campus Universitaire, Tunis El-Manar 2092,
Tunisia.
Institut fu¨r Anorganische und Analytische Chemie, Technische
(2)
Universita¨t Braunschweig, Braunschweig 38023, Germany.
To whom correspondence should be addressed; e-mail:
Synthesis of N-benzimidazol-2-yl Nꢁ-amidine
2. The benzimidazole-2-yl moiety acts as an
∗
rdnnin@fst.rnu.tn
381
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1074-1542/07/0600-0381/0 2007 Springer Science+Business Media, Inc

382
Raouafi, Freytag, Jones, and BenKhoud
N
N
N
AcOH catal.
Reflux 3h
NH2
N
C2H5 C(OEt)3
+
N
C2H5
H
H
EtO
1
Scheme 1.
electron-withdrawing group which hardens the
imidic carbon of the imidate 1, allowing it to react
with benzylamine, at room temperature, to give
the corresponding amidine 2 after the substitution
of the ethoxy group by a benzylamine moiety in
very good yield10,11 (87%) (Scheme 2).
Results and discussion
Spectroscopic study
The structures of the imidate 1 and the corre-
sponding amidine 2 have been readily confirmed
by the analysis of their IR and NMR spectra.
IR spectra show the presence of a new band at
3170 cm−1 associated with the amidinic N–H
stretching vibration, and a lower frequency shift
Preparation and physical data of the amidine 2
0.64 g of benzylamine (6.0 mmol) was
slowly added to a solution containing 1.10 g of
the imidate 1 (5.07 mmol) dissolved in 15 mL
of ethanol. The mixture was stirred at room tem-
perature for 24 h. The resulting product 2 was fil-
tered off and recrystallized from ethanol as colour-
less prisms (1.21 g, 87%). m.p. 161–162◦C. IR
(CHCl3): νNH = 3462 cm−1, νNH = 3167 cm−1,
=
is observed for the C N vibration appearing to-
ward 1615 cm−1 (c.f νC N 1653 cm−1 for imidate
=
(1). The 1H NMR spectra show no signals for the
ethoxy group, but instead a doublet at 4.5 ppm and
newaromatic protons assignedtothebenzylgroup
are observed with no doubling patterns. The 13C
NMR spectra show a new peak at about 46 ppm
attributed to the carbon of the methylene group,
and a lower field shift of the imidic carbon signal
(164 ppm versus 167 ppm).
νC N = 1615 cm−1. 1H NMR (CDCl3, 300 MHz):
=
1.3 (t, CH3, 3H), 2.5 (q, CH3–CH2, 2H), 4.7 (s,
=
Ph–CH2, 2H), 7.1–8.2 (mu, C CH, 9H), 11.2 (br,
NH, 1H), 12.3 (br, NH, 1H). Proton decoupled 13C
NMR (CDCl3, 75 MHz): 11.0, 25.8, 45.9, 121.2–
128.0, 133.3, 138.0, 157.9, 164.2.
Conformational study
In order to determine the most stable con-
former of the amidine compound 2, an X-ray study
is undertaken (Table 1) (Scheme 3).
Crystal structure determination
Experimental results show that the amidine
2 crystallizes in monoclinic system with space
group P21/c as ZsZ conformer (Fig. 1). The benz-
imidazole group which is conjuguated to the three
Data were collected at T = 133(2) K on a
Bru¨ker SMART 1000 CCD. The structure was
solved and refined on F2 using SHELXS 97 and
SHELXL 97 programs.12,13
N
N
absolute EtOH
Bn-NH2
N
+
N
87 %
N
N
H
EtO
H
HN
1
2
Ph
Scheme 2.

Synthesis structural studies of imidate N-(1H-benzimidazol-2-yl)-Nꢀ-benzyl propionamidine 383
Table 1. Crystal Data and Structure Refinement
Empirical formula
Formula weight
Wavelength (λ)
C17H18N4
278.35
˚
0.71073 A (Mo Kα graphite
monochromated)
Monoclinic
P21/c
Crystal system
Space group
Unit cell dimensions
˚
a (A)
10.7913(10)
15.5164(14)
9.1130(8)
108.378(3)
1448.1(2)
4
1.277
0.079
592
˚
b (A)
˚
c (A)
β (◦)
3
˚
Volume (A )
Z
Density (calculated, Mg/m3)
Absorption coefficient (mm−1
F(000)
Fig. 1. Ellipsoid representation of the amidine 2 in 50% prob-
)
ability.
Crystal size (mm)
0.39 × 0.38 × 0.27
Theta range for data collection (◦) 1.99 to 30.03
N4–H4· · ·N1 = 137.5◦] and an intermolecular
Index ranges (h, k, l)
−15 < h < 14, −21 < k < 21,
−12 < l < 12
19064
hydrogen bond linking H2 and N3ꢁ atoms
Reflections collected
[N2–H2 = 0.89 A, N3ꢁ· · ·H2 = 2.145 A,
˚
˚
Independent reflections
Completeness to theta = 30.00◦
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
4249 [R(int) = 0.0337]
ꢁ
ꢁ
◦
˚
99.9%
N2· · ·N3 = 3.024 A, N3 · · ·H2–N2 = 170.7 ]
4249/0/199
1.041
R1 = 0.0414, wR2 = 0.1128
R1 = 0.0488, wR2 = 0.1185
0.349 and −0.206
246820
are observed (Table 2). Furthermore, the N3–C8
˚
bond length (1.3257(12) A) is longer than the
=
standard value for a pure unconjugated C N
−3
˚
14
Largest diff. peak and hole (eA
CCDC deposit number
)
˚
double bond (1.27 A) and the C8–N4 bond
˚
length (1.3361(13) A) is close to that of N3–
CCDC-246820 contains the supplementary crystallographic data for
this paper. These obtained free of charge via www.ccdc.cam.ac.uk/
data request/cif, by e-mailing: data request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033.
C8 and shorter than a standard single C–N bond
(1.47 A). These observations suggest that the
15
˚
multiple bonding electrons are delocalised over
the three centers of the amidine function. The
N3–C8–N4 angle value of 124.64(8)◦ shows an
appreciable deviation from the expected value of
120.0◦ for an sp2-hybridized carbon (Table 2).
This may be explained by both the asymmetric
substitution and the electronic repulsion of the
nitrogen lone pairs.16
centres of the amidine function are nearly planar
because of the presence of benzimidazolic moiety
(ꢀ[C7–N1–C1–C2] = 179.56◦, ꢀ[C6–N2–C7–
N3] = 179.25◦ and ꢀ[C7–N3–C8–N4] = 0.59◦).
Moreover an intramolecular hydrogen bond,
˚
The above mentioned hydrogen bonding
leads to inversion-symmetric dimers (Fig. 2).
between H4 and N1 atoms [N4–H4 = 0.92 A,
˚
˚
N1· · ·H4 = 1.864 A, N4· · ·N1 = 2.618 A,
Scheme 3.

384
Raouafi, Freytag, Jones, and BenKhoud
◦
˚
Table 2. Selected Bond Lengths (A) and Angles ( )
˚
Bond lengths (A)
N1–C7
N1–C1
N3–C8
N3–C7
1.3302(12)
1.3886(12)
1.3257(12)
1.3755(11)
1.3942(13)
1.3894(15)
N2–C7
N2–C6
N4–C8
N4–C11
C11–C12
C12–C13
1.3740(12)
1.3881(12)
1.3361(13)
1.4578(12)
1.5156(13)
1.3913(14)
C1–C2
C2–C3
Bond angles (◦)
C7–N1–C1
C8–N3–C7
N1–C1–C2
N2–C6–C1
N1–C7–N2
N2–C7–N3
N3–C8–C9
C8–C9–C10
105.04(8)
119.16(8)
129.09(9)
105.34(8)
112.68(8)
119.05(8)
116.13(8)
111.61(9)
C7–N2–C6
C8–N4–C11
N1–C1–C6
N1–C7–N3
N3–C8–N4
N4–C8–C9
106.81(8)
126.34(8)
110.12(8)
128.26(8)
124.64(8)
119.19(8)
Fig. 3. HF/6-311G optimized geometry of the amidine 2.
N4–C11–C12 114.03(8)
N2–C6–C5 133.29(10)
dine 2 was optimized by semi-empirical MOPAC
PM3 calculations20 and refined by ab initio
method using HF/6-31G basis for the two tau-
tomers and HF/6-311G basis for tautomer 121
(Fig. 3) and for the two conformers 1 and 2
(Scheme 4).
Comparative study
Quantum mechanics calculations applied for
amidines allow the determination of their struc-
tural proprieties.17–19 The geometry of the ami-
Fig. 4. MOPAC PM3 optimized geometry of the amidine
Fig. 2. Amidine 2 in its dimeric form inside the crystal.
dimer.

Synthesis structural studies of imidate N-(1H-benzimidazol-2-yl)-Nꢀ-benzyl propionamidine 385
H
H
N
N
N
N
H
N
N
N
N
H
Tautomer 2
Tautomer 1
Ph
Ph
Scheme 4.
According to Table 3, it seems that values
found when an extended basis is used are the near-
est to the experimental results e.g. the N3–C8–N4
angle value is 124.44◦ based on HF/6-311G basis
results, whereas the HF/6-31G basis gives the val-
ues of 123.77◦ and 119.75◦ for the two tautomers
(1) and (2), respectively while the experimental
value is 124.64◦. The same conclusions can be
drawn for the N3–C8 and N4–C8 bond lengths.
Moreover, the calculated intramolecular hydro-
gen bond length for the conformer 1 is different
from the experimental value; it is about 2.2 times
longer than the experimental data (Fig. 4). The
formation of the tautomer 2 is disadvantaged by
the absence of a hydrogen bond. The calculated
charges, using the HF/6-311G basis results, are
−0.65 e, −0.63 e and −0.43 e for the nitrogen
N1, N2 and N4, respectively. This may explain
their good reactivity toward electrophilic com-
pounds such as isothiocyanate, N-sulfinylamine
and tris(dimethylamino)phosphine.6,7
Conclusions
The knowledge of the nature of the N–
=
C N bond type of the amidine function is im-
portant in biological processes, and especially
when this function is associated to an impor-
tant pharmacophore group like as benzimidazole.
In this article, a new benzimidazole compound,
N-benzimidazol-2-yl Nꢁ-benzyl proponamidine 2,
has been synthesized and structurally character-
1
ized. IR, H NMR, 13C NMR and X-Ray data
Table 3. Experimental and Calculated Values for Some Parameters of the Amidine 2
Parametersa
X-Ray
Tautomer 1 /HF 6-31G Tautomer 2/HF 6-31G Tautomer 1/HF 6-311G
d[N2–C7]
d[N3–C7]
d[N3–C8]
d[C8–N4]
1.3740
1.3755
1.3257
1.3361
106.81
124.64
119.05
111.61
−0.94
179.56
172.07
0.59
1.3836
1.3642
1.2992
1.3477
107.95
123.77
118.55
114.46
0.03
179.98
−179.70
−1.15
1.940
1.3033
1.3734
1.3825
1.2683
105.12
119.75
122.36
112.12
0.006
179.98
178.76
0.93
1.3695
1.3672
1.3029
1.3435
107.89
124.44
118.44
111.96
0.01
θ[C6–N2–C7]
θ[N3–C8–N4]
θ[N2–C7–N3]
θ[C8–C9–C10]
ꢀ[C3–C4–C5–C6]
ꢀ[C7–N1–C1–C2]
ꢀ[C8–N3–C7–N2]
ꢀ[C7–N3–C8–N4]
d[N4–H4...N1]
For the dimer form
Parametersb
179.99
179.97
0.16
0.921
–
1.966
X-Ray
0.887
170.71
PM3 calculated values
2.422
170.7
d[N2–Hꢁ2· · ·N3]
θ[N2–H2—Nꢁ3]
a
◦
˚
Bond length in A (d); bond angles (θ), dihedral angles (ꢀ) in deg( )
bThe dimer form

386
Raouafi, Freytag, Jones, and BenKhoud
9. Ostrowski, S. Molecules 1999, 4, 287.
10. Yahya-Zadeh, A.; Booth, B.L. Synthetic Commun. 2001, 31,
3617.
assigned the structure of the designed compound
as expected.
The molecular structure of 2 was studied us-
ing PM3 sem-iempirical method and ab-initio cal-
culations and compared these with experimental
data to assess the accuracy of the theoretical meth-
ods. The different structural data obtained from X-
ray diffraction are in good agreement with those
from quantum mechanics calculations.
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Acknowledgments
solution; University of Go¨ttingen, Germany, 1997.
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Authors wish to think “Le MINISTERE
DE LA RECHERCHE SCIENTIFIQUE, DE LA
TECHNOLOGIE ET DU DEVELOPPEMENT
DES COMPETENCES (Lab-CH02)” for finan-
cial support. Prof. Reinhard Schmutzler and Prof.
Khaled Boujlel are acknowledged for their helpful
discussion of this work.
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