Tautomeric equilibria in solutions of 1-methyl-2-phenacylbenzimidazoles

Article abstract of DOI:10.1016/j.molstruc.2016.12.050

Until now the susceptibility of 1-methyl-2-phenacylbenzimidazoles to the proton transfer has not been carefully examined. There only have been selective trials to recognize tautomeric equilibrium of substituted compounds. Unfortunately, conclusions of the

Full text of DOI:10.1016/j.molstruc.2016.12.050

Accepted Manuscript
Tautomeric equilibria in solutions of 1-Methyl-2-phenacylbenzimidazoles
Agnieszka Skotnicka, Przemysław Czeleń, Ryszard Gawinecki
PII:
S0022-2860(16)31367-9
10.1016/j.molstruc.2016.12.050
MOLSTR 23248
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 3 June 2016
Revised Date: 7 November 2016
Accepted Date: 19 December 2016
Please cite this article as: A. Skotnicka, P. Czeleń, R. Gawinecki, Tautomeric equilibria in solutions
of 1-Methyl-2-phenacylbenzimidazoles, Journal of Molecular Structure (2017), doi: 10.1016/
j.molstruc.2016.12.050.
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Graphical abstract
R
H
O
R
O
N
N
N
N
CH3
CH3
K
O
R = p-N(CH3)2 (1), p-OCH3 (2), p-CH3 (3), m-CH3 (4), H (5), p-Br (6), m-Cl (7), p-NO2 (8)

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Tautomeric Equilibria in Solutions
of 1-Methyl-2-Phenacylbenzimidazoles
Agnieszka Skotnickaa*, Przemysław Czeleńb and Ryszard Gawineckia
a
Department of Chemistry, University of Science and Technology, Seminaryjna 3, 85-326
Bydgoszcz, Poland
b
Department of Physical Chemistry, Faculty of Pharmacy, Collegium Medicum, Nicolaus
Copernicus University, Kurpinskiego 5, 85-950 Bydgoszcz, Poland
* Corresponding author’s e-mail address: askot@utp.edu.pl
Abstract: Until now the susceptibility of 1-methyl-2-phenacylbenzimidazoles to the proton
transfer has not been carefully examined. There only have been selective trials to recognize
tautomeric equilibrium of substituted compounds. Unfortunately, conclusions of these studies
are often conflicting. Therefore, the aim of this work was to analyze the influence of the
factors affecting the tautomeric processes of substituted 1-methyl-2-phenacylbenzimidazoles
1
in solutions of chloroform by spectroscopic technique of H and 13C NMR. Complex
equilibria may only take place when molecules of tautomeric species contain multiple basic
and/or acidic centres. Analysis of NMR spectra show unequivocally that 1-methyl-2-
phenacyl-benzimidazoles (ketimine tautomeric form) are in equilibrium with (Z)-2-(1-methyl-
1H-benzo[d]imidazol-2yl)-1-phenylethenols (enolimine).
Keywords: phenacylbenzimidazoles, tautomerism, substituent effect, hydrogen bond, NMR,
quantum-chemical calculations.
Introduction
Benzimidazoles and imidazoles are widely used as the substrates in synthesis of
organic compounds, mostly heterocyclic [1]. Derivatives of benzimidazoles deserve attention
because these compounds show significant biological activity [2]. They act, e.g., in the

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antibacterial way [3,4], destroy parasites [5], are antiallergic [6] and show anti-tumour action
[7]. Besides, a fragment of 5,6-dimethylbenzimidazole is a component of vitamin B12 [8].
Some of 1-methyl-2-phenacylbenzimidazoles were synthesized according to reaction
of benzoyl substituted mercaptals with N-methyl-o-phenylenediamine [9,10]. Unfortunately,
the synthesis requires a usage of relatively inconvenient substrates and with the release of
methanethiol. Aforementioned synthesis, as well as other earlier described in the literature
[11,12], are characterized by low yield, therefore, we prepared compounds 1,7 and 8
according to slightly modified reaction using 1,2-dimethylbenzimidazole with substituted
ethyl or methyl benzoate and excess of sodium hydride [1]. On the other hand, compounds 2-
6 were prepared by using a method based on conversion of 2-phenacylbenzoxazoles [13] and
2-phenacylbenzimidazoles [14].
Until now the susceptibility of 1-methyl-2-phenacylbenzimidazoles to the proton
transfer has not been carefully examined. There have been selective trials to recognize
tautomeric equilibrium of substituted compounds. Unfortunately, conclusions of these studies
are often conflicting. In the majority of cases, the literature reports reveal that 1-methyl-2-
phenacylbenzimidazoles (ketimine) are in equilibrium with enaminone tautomers [9-12,14].
However, some studies [15] suggest that these compounds occur only in enolimine form.
Therefore, divergence and insufficient literature data led us to investigate factors influencing
tautomeric equilibria in solutions of 1-methyl-2-phenacylbenzimidazoles.
Complex equilibria may only take place when molecules of tautomeric species contain
multiple basic and/or acidic centres. 2-acylmethylpyridines are capable of being transformed
into their tautomers [16-21]. The molecules of these compounds contain a specific moiety
(Scheme 1) that enables transfer of the methylene proton to the oxygen and nitrogen atoms
(basicity centres).
CH
O
N
C
R
H2
Scheme 1. 4-(Methyleneamino)hex-4-en-2-one moiety
This particular moiety is also present in some other phenacyl substituted heterocycles.
Recently, we found that 2-phenacylbenzoxazoles (ketimine form) are in equilibrium with (Z)-
2-(benzo[d]oxazol-2-yl)-1-phenylethenols (enolimine form) in chloroform (CDCl3) solutions
[13]. Molar ratio of these tautomers depends significantly on substitution. Thus, the strong

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electron-donating substituents were found to stabilize the ketimine tautomer. The MP2 ab
initio calculations supported our experimental finding, where the enolimine tautomer with the
intramolecular OH…N hydrogen bond was observed to be more stable than enaminone, i.e.,
(E)-2-(benzo[d]oxazol-2(3H)-ylidene)-1-phenylethanone. 13C CPMAS NMR spectral data
revealed that the p-NMe2-substituted ketimine tautomer is the only form present in the
crystalline state. On the other hand, in our studies enolimine form was detected when the
substituent has either an electron-donor character or electron-acceptor one [13].
It is well known that minor modifications in the molecule may significantly affect the
tautomeric equilibria [13,16,17,21,22]. This work describes chemical experiments and
quantum-chemical calculations to determine tautomeric equilibria recorded in CDCl3
solutions of 1-methyl-2-phenacylbenzimidazoles. The detailed methodologies used to prepare
material for NMR spectra and then theoretical studies have been considered in the following
section.
Material and Methods
1,2-dimethylbenzimidazole was prepared by the known method [23]. Other used
substrates were purchased from Sigma-Aldrich. Melting points were measured on a Boetius
table and are uncorrected. Satisfactory elemental analyses (± 0.30 % for C, H and N) were
obtained for all prepared compounds.
Syntheses
Slightly modified procedure [9] was used to prepare compounds 1,7 and 8. Thus, a
mixture of 1,2-dimethylbenzimidazole (0.29 g, 2 mmol), substituted ethyl or methyl benzoate
(2 mmol), dry benzene (10 mL), dimethylformamide (0.5 mL) and sodium hydride (0.15 g of
its 60% suspension in mineral oil) was refluxed and stirred magnetically overnight. The
reaction was quenched by addition of water (15 mL) and the resulted mixture was extracted
with ethyl acetate (20 mL). The organic layer was subsequently washed with water (2 x 10
mL) and brine (2 x 10 mL) and dried with sodium sulfate. Solid impurities were filtered off,
the filtrate was concentrated on the rotary evaporator and the obtained solid was recrystallized
from ethanol.
On the other hand, compounds 2-6 were prepared by treating 1,2-dimethylbenz-
imidazole with benzoyl chlorides in the presence of triethylamine followed by thermal
decomposition of formed 2-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-phenylvinyl benzoates.

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Thus, substituted benzoyl chloride (8 mmol) was added at once to the mixture of 1,2-
dimethylbenzimidazole (0.29 g, 2 mmol), triethylamine (0.81 g, 8 mmol) and diglyme (10
mL) and the resulted mixture was heated (steam bath) and stirred overnight. Addition of water
(6 mL) precipitated the byproduct. Solution of morfoline (0.52 g, 6 mmol) in methanol (3 mL)
was added to crude 2-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-phenylvinyl benzoate and the
resulted mixture was refluxed for 5 minutes. Reaction was quenched by addition of water (3
mL) and the precipitated solid product was recrystallized from ethanol.
Products characteristics are compiled in Table 1. Here there is an elemental analysis of the
aforementioned compounds:
1: C18H19N3O (293.36): calcd. C 73.69, H 6.53, N 14.32; found C 73.54, H 6.41, N 14.39.
2: C17H16N2O2 (280.32): calcd. C 72.84, H 5.75, N 9.99; found C 72.91, H 5.65, N 9.86.
3: C17H16N2O (264.32): calcd. C 77.25, H 6.10, N 10.60; found C 77.12, H 6.23, N 10.67.
4: C17H16N2O (264.32): calcd. C 77.25, H 6.10, N 10.60; found C 77.17, H 6.16, N 10.54.
5: C16H16N2O (250.3): calcd. C 76.78, H 5.64, N 11.19; found C 76.83, H 5.66, N 11.23.
6: C16H13BrN2O (329.19): calcd. C 58.38, H 3.98, N 8.51; found C 58.31, H 3.96, N 8.47.
7: C16H13ClN2O (284.74): calcd. C 67.49, H 4.60, N 9.84; found C 67.52, H 4.62, N 9.94.
8: C16H13N3O3 (295.29): calcd. C 65.08, H 4.44, N 14.23; found C 65.09, H 4.42, N 14.21.
NMR spectra
The 1H and 13C NMR spectra were recorded for diluted CDCl3 solutions at 298 K on a
Bruker Avance 400 FT NMR spectrometer. The chemical shifts are referenced to the signal of
13
internal TMS at δ=0.00 ppm. The solid state C CPMAS (cross-polarization, magic angle
spinning) NMR spectra were recorded on the same spectrometer using the samples packed in
4.0 mm o.d. zirconia rotors. The samples were spun at 12 kHz rate and >1000 transients were
accumulated. The acquisition time for compound 2 was 0.034 sec and for compound 8 was
0.025 sec. The FIDs are apodized by 10 Hz exponential window before FT. The shifts are
referenced to the C=O signal of glycine standard at δ = 176.03 ppm. Spectra are available in
Supplementary material.
Quantum-chemical calculations
Geometries for the isolated molecules (vacuum) of the tautomers were optimized
using the second order Möller-Plesset method (MP2) [24,25]. Computations were carried out
utilizing the split-valence triple-zeta basis sets 6-311+G(d,p) [26]. The chemical shifts of
carbon and hydrogen atoms (relative to TMS, ppm) were evaluated by gauge invariant atomic

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orbitals (GIAO) method at the B3LYP/ cc-pVTZ level of theory by using the PCM model
[27]. All calculations were performed with use of Gaussian 09 package [28].
The figure of molecules was prepared with Dassault Systèmes BIOVIA, Discovery Studio
Modeling Environment [29].
Results and Discussion
1-methyl-2-phenacylbenzimidazoles were earlier prepared by at least two different
methods [9-12,30]. 1,2-dimethylbenzimidazole and substituted alkyl benzoates or benzoyl
chlorides were used as substrates in the present paper (Scheme 2). Moreover, usage of the
base (sodium hydride or triethylamine) was necessary to abstract proton from the 2-methyl
group (this step was then followed by benzoylation).
O
N
N
N
N
1. NaH
R
CH3
2. R-C6H4-CO2Alk
CH3
CH3
1,7,8
R
O
O
O
N
N
N
N
N
1. NEt3
∆
R
R
CH3
2. R-C6H4-COCl
N
CH3
CH3
CH3
R = p-N(CH3)2 (1), p-OCH3 (2), p-CH3 (3), m-CH3 (4), H (5), p-Br (6), m-Cl (7), p-NO2 (8)
Scheme 2. Synthesis of 1-methyl-2-phenacylbenzimidazoles
The ketimine form, K, of 1-methyl-2-phenacylbenzimidazoles (Scheme 3) was
expected to tautomerize into enolimine, (Z)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-
phenylethenol (O) and enaminone, (E)-2-(1-methyl-1H-benzo[d]imidazol-2(3H)-ylidene)-1-
phenylethanone (E). Both O and E tautomers included in Scheme 3 are stabilized by
intramolecular hydrogen bonds.

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12
O
15
14
H
R
O
R
1
N
7
4
13
16
17
8
9
N
6
5
11
2
10
18
3
N
N
CH3
CH3
19
K
E
R
H
O
N
N
CH3
O
Scheme 3. Tautomeric equilibria of 1-methyl-2-phenacylbenzimidazoles
Two different tautomers are often found to be formed during recrystallization (Table
1). According to Huang and Wang these species can be separated by fractional crystallization.
The K (ketimine) and O (enolimine, misnamed as E, i.e. enaminone) appear as colourless and
pale yellow crystals, respectively. Based on IR spectral data (KBr tablets), it was observed
that these species differ from each other as follows: 1630 cm-1 (C=O) for O and ca 1670 cm-1
(C=O) for K. On the other hand, only the K form was obtained during recrystallization of the
p-methoxy derivative [9,10]. Our studies of the same derivative, which were performed in the
solid state by using 13C CPMAS NMR, revealed that p-methoxy-substituted ketimine
tautomer (compound 2) is the only present form in the crystalline state. On contrary to the 13C
CPMAS NMR spectra for compound 8 (with the p-nitro substituent), which show only
enolimine form (Table 2).
Table 1. Overall reaction yields (with respect to 1,2-dimethylbenzimidazole) and melting
points of compounds 1-8
Compound Yield (%)
mp (ºC)
Products characteristics
36
45
228-230
139-142
yellow prisms
white needles
1
2
135-136e [9-10]

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101-104 and 154-156
131-132a and 122-123b [9]
109-110
119-121c and 149-152d
150-151a and 134-134.5b [9]
150-152 [11,12], 150.0-151.5
[14,30]
35
yellow prisms
3
24
40
yellow prisms
pale yellow prisms
and colorless needles
4
5
83
57
80
120-123 and 157-158
135-137
greenish needles
yellow prisms
orange needles
6
7
8
207-210
a,b Mp’s of different tautomeric forms (see Discussion).
c Plates.
d Needles.
e Mp of the K tautomeric form [9,10].
Values of C11 chemical shift reveal that not only K tautomer is present in CDCl3
solution but also O tautomer [31]. The downfield signal of the acidic protons confirms that
the enolimine tautomer is therefore present in solution [13]. During our studies, OH protons
were observed at ca 13 ppm in chloroform, while the resonance at ca 12 ppm in CDCl3 was
assigned to the O form (enolimine, misnamed as E, i.e. eneminone) by Huang et al. [9,10] and
ca 14 ppm in DMSO-d6 by Dzvinchuk [14].
1
Table 2. Selected calculated (italic) (B3LYP/cc-pVTZ) and experimental H and 13C NMR
chemical shifts for 1-methyl-2-phenacylbenzimidazoles and their tautomers (solutions in
CDCl3)
Tautomer
H10
C2
C10
C11
H19
C19
O‒H
4.65
5.75
4.83
4.44
149.40
153.99
148.56
156.93
145.74b
37.95
77.22
37.94
46.00
42.26b
190.66
a
3.75
a
30.85
a
1K
1O
2K
a
191.38
201.96
196.06b
3.86
3.94
30.94
32.46
31.18b

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5.83
6.32
5.02
5.82
4.72
5.89
4.95
4.60
5.91
6.49
4.81
5.82
5.34
5.84
4.73
4.59
5.59
6.68
154.57
162.89
148.42
154.47
148.8
75.65
84.86
37.91
76.57
39.02
77.2
174.96
173.21
192.21
174.83
194.16
174.38
192.54
204.16
174.82
173.59
192.73
174.70
191.27
175.01
190.88
204.02
174.17
169.92
164.46b
3.66
3.76
3.80
3.61
3.75
3.66
3.83
4.03
3.68
3.80
3.78
3.64
3.91
6.69
a
29.12
30.67
31.95
29.15
30.40
29.08
30.88
32.65
29.16
30.77
31.87
29.06
31.92
29.18
31.95
32.53
29.30
31.03
31.96
a
2O
14.53
3K
3O
4K
4O
5K
a
154.39
148.27
157.03
154.41
162.45
148.10
154.10
143.7
13.74c
38.17
46.11
76.94
86.41
38.68
76.15
37.92
76.25
a
13.83c
5O
14.58
6K
6O
7K
7O
8K
13.19c
a
154.14
148.42
155.60
153.82
161.10
147.93b
46.49
77.45
91.29
87.29b
3.89
3.75
3.84
13.36c
8O
14.69
a Signal not observed.
b The respective 13C CPMAS chemical shifts.
c Very broad signal.
Content of the ketimine form in chloroform solutions of 1-methyl-2-phenacylbenz-
imidazoles can be found in Table 3 (it is based on integrals of the H10 and H19 signals).
π
-
electron delocalization was found to be the main reason responsible for the tautomeric
preferences of 2-phenacylpyridines [16] (other effects such as strength of the intramolecular
hydrogen bond should also be taken into account). Other numerous phenacyl derivatives can
be also sufficiently stabilized by the electron-donor substituent (Scheme 4). Unfortunately, the
linear correlations of amount of the tautomer with the substituent constants [32] are of rather
low quality (linear correlation coefficient ≤ 0.8).
Table 3. Content of the K form (%) in CDCl3 solutions

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Ka
Kb
100
65
63
29
32
14
c
83
65
64
29
33
14
c
1
2
3
4
5
6
7
8
4
0
a Based on integrals of the H10 signals.
b
Based on integrals of the H19 signals.
c Unrecurring data.
N
N
R
O
Me
Scheme 4. Stabilization of the ketimine form by electron-donor substituent
Quantum-chemical calculations
In our work, obtained experimental data were compared with the results of the
quantum-chemical calculations. The MP2 procedure is recommended as the most accurate
and effective ab initio method for studying the medium size molecules involving hydrogen
bonds [33]. It includes electron correlation, so the calculated and experimental data are
expected to be comparable [34]. Some optimized bond lengths and dihedral angles in the
molecules of 1-methyl-2-phenacylbenzimidazoles and their tautomers are presented in Table
4, where hydrogen bond is shorter in the enolimine form than in the enaminone form.
Additionally, hydrogen bond angles and the distances between atoms N1 and O2 are greater
in the O tautomer than E tautomer. Therefore, based on the geometry of hydrogen bond
[35,36], it can be concluded that the enolimine form is more stable than enaminone form.
It can be stated that the substituent only slightly affects the conformation of each
tautomer (Table 4). The carbonyl group is twisted with respect to the neighbouring benzene
ring by ca 30° (in general, this twist is independent on tautomer). The six-membered pseudo

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rings including the intramolecular hydrogen bonds in both enolimines and enaminones are
almost planar.
Fig. 1. Optimized structures of selected 1-methyl-2-phenacylbenzimidazoles
Table 4. Selected calculated (MP2/6-311+(d,p) bond lenghts [Å], distances between atoms
[Å] and interplanar angles [deg] in 1-methyl-2-phenacylbenzimidazoles and their tautomers
N1…H12 (in O)
O12−H12 (in O)
or
N1…O12
N1H12O12 C14C13C11O12
C18C13C11O12
or
O12…H1 (in E)
N1−H1 (in E)
-
-
-
-
-22.87
-28.35
-29.39
-24.72
-31.62
-31.62
-284.98
-28.35
-30.02
2K
2O
2E
5K
5O
5E
8K
8O
8E
0.99
1.03
-
1.71
1.82
-
2.62
2.60
-
148.89
129.74
-
0.99
1.03
-
1.72
1.82
-
2.62
2.60
-
148.79
129.84
-
0.99
1.03
1.71
1.82
2.62
2.60
148.81
129.84

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The calculated energies of different tautomers (Table 5) show that the K form is the
most stable (both electron-donor and electron-acceptor substituents follow this rule). The O
Table 5. MP2(6-311+G(d,p) calculated relative
energies [kJ mole-1] of different tautomers
0.00a
2K
12.55
33.47
0.00b
12.55
33.47
0.00c
8.37
2O
2E
5K
5O
5E
8K
8O
8E
25.10
a Absolute energy: -915.0265 Hartree.
b Absolute energy: -800.7661 Hartree.
c Absolute energy: -1004.8717 Hartree.
form is always less stable than ketimine (the more electronacceptor is the substituent, the
more stable is the enolimine form). Thus, the order of stability of these two tautomers is
reversed with respect to 2-phenacylbenzoxazoles [13]. In spite of the fact that both E and O
are stabilized by rather strong [37-40] intramolecular hydrogen bonds, only E tautomer is
unstable (both electron-donor and electron-acceptor substituents follow the rule). It is
noteworthy that in molecule of enolimine tautomer, benzen is aromatic and pseudo ring with
hydrogen bond is quasi-aromatic, while imidazole ring probably is aromatic; on the other
hand, in the enaminone molecule, it is only the case for benzene and pseudo ring (Scheme 3).
Therefore, O seems to be more stable than E.
Conclusions
Indicated aims were achieved through the synthesis of a series of substituted
derivatives of 1-methyl-2-phenacylbenzimidazoles. Tautomeric forms were identified on the

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basis of magnetic nuclear resonance spectra of 1H and 13C isotopes. 1-methyl-2-
phenacylbenzimidazoles (ketimine, K) were found to be in equilibrium in chloroform
solutions with their enolimine tautomeric forms, i.e., 2-(1-methyl-1H-benzo[d]imidazol-2yl)-
1-phenylethenols (O). No 2-(1-methyl-1H-benzo[d]imidazol-2(3H)-ylidene-1-phenyl-
ethanones (enaminone tautomer, E) were detected. Therefore, content of the ketimine form
strongly depends on substituent, where electron-donor groups present in the molecule
stabilize this form. The obtained experimental data were compared with the results of the
quantum-chemical calculations. The MP2 calculated energies support the observed tautomeric
preferences (both electron-donor and electron-acceptor substituents follow the rule).
Although, both O and E tautomers are stabilized by intramolecular hydrogen bonds, the
geometry of hydrogen bond indicates that the enolimine form is more stable than enaminone
form. Thus, the most labile tautomer is always enaminone.
Conflict of interest
The authors confirm that this article's content has no conflicts of interest.
Acknowledgments
This research was supported in part by PL-Grid Infrastructure.
References
[1] M. O. Lozinskii, A. Y. Il’chenko, Chemistry of heterocyclic compounds at the
Institute of Organic Chemistry National Academy of Sciences of Ukraine (Review),
Chem. Heterocycl. Comp 45 (2009) 376-399
[2] A. O. H. El-Nezhawy, S. T. Gaballah, M. A. A. Radwan, A. R. Baiuomy, O. M. E.
Abdel-Salam, Structure-Based Design of Benzimidazole Sugar Conjugates: Synthesis,
SAR and In Vivo Anti-inflammatory and Analgesic Activities, Med Chem. 5 (2009)
558-569
[3] P. S. Charifson, A. L. Grillot, S. Bellon, T. H. Grossman, J. D. Parsons, M. Badia, D.
D. Deininger, J. E. Drumm, C. H. Gross, A. L. Tiran, Y. Liao, N. Mani, D. P. Nicolau,
E. Perola, S. Ronkin, D. Shannon, Q. Tang, L. L. Swenson, P. R. Tessier, S. K. Tian,
M. Trudeau, T. Wang, Y. Wei, H. Zhang and D. Stamos, Novel dual-targeting
benzimidazole urea inhibitors of DNA gyrase and topoisomera se IV
possessing potent antibacterial activity: Intelligent design and evolution

13
ACCEPTED MANUSCRIPT
through the judicious use of structure-guided design and stucture-activity
relationships, J. Med. Chem. 51 (2008) 5243-5263
[4] T. C. Kühler, M. Swanson, B. Christenson, A. Ch. Klintenberg, B. Lamm, J. Fägerhag,
R. Gatti, M. O. lwegard-Halvarsson, V. Shcherbuchin, T. Elebring, J. E. Sjöström,
Novel Structures Derived from 2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazole as Anti-
Helicobacter pylori Agents, Part 1, J. Med. Chem. 45 (2002) 4282-4299
[5] R. D. Haugwitz, B. V. Maurer, G. A. Jacobs, V. L. Narayanan, Antiparasitic agents. 3.
Synthesis and anthelmintic activities of novel 2-pyridinyl-5-isothiocyanatoben-
zimidazoles, J. Med. Chem. 22 (1979) 1113-1118
[6] J. H. Musser, R. E. Brown, B. Love, K. Bailey, H. Jones, R. Kahen, F. Huang, A.
Khandwala, M. Leibowitz, P. Sonnino-Goldman, D. Donigi-Ruzza, Synthesis of 2-
(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl) benzo heterocycles. A novel series of orally
active antiallergic agents, J. Med. Chem. 27 (1984) 121-125
[7] N. R. Thimmegowda, S. N. Swamy, C. S. A. Kumar, Y. C. S. Kumar, S. Chandrappa,
G. W. Yipb, K. S. Rangappa, Synthesis, characterization and evaluation of
benzimidazole derivative and its precursors as inhibitors of MDA-MB-231 human
breast cancer cell proliferation, Bioorg, Med. Chem. Lett. 18 (2008) 432-435
[8] A. A. Spasov, K. V. Lenkskaya, P. M. Vasil'ev, Molecular-biological problems of
drug design and mechanism of drug action. Hypoglycemic potential of benzimidazole
derivatives, Pharmaceutical Chemistry Journal 49 (2015) 495-500
[9] Z.-T. Huang, M.-X. Wang, The synthesis and tautomerization of ketene aminals with
benzimidazoline ring, Tetrahedron 48 (1992) 2325-2332
[10]
Z.-T. Huang, M.-X. Wang, A New Route to 3H-1,5-Benzodiazepines and
Heterocylic Ketene Aminals from Benzoyl Substituted Ketene Dithioacetals and
Diamines, Synthesis 12 (1992) 1273-1276
[11]
D. Nardi, R. Pennini, A. Tajana, Heterocyclic compounds from 3,3-
dimercapto-1-aryl-2-propen-1-ones. Note 3. Condensation with N-methyl-o-
phenylenediamine and N-benzyl-o-phenylenediamine, J. Heterocycl. Chem. 12 (1975)
825-828
[12]
J. Davoll, The reaction of o-phenylenediamine with αβ-unsaturated acids and
with β-keto-esters, J. Che,. Soc. (1960) 308-314
[13]
A. Skotnicka, E. Kolehmainen, P. Czeleń, R. Gawinecki, A. Valkonen,
Tautomeric equilibria in solutions of 2-phenacylbenzoxazoles, Int. J. Mol. Sci. 14
(2013) 4444-4460

14
ACCEPTED MANUSCRIPT
[14]
B. Dzvinchuk, A. M. Nesterenko, V. V. Polovinko, A. B. Ryabitskii, M. O
Lozinskii, Synthesis and tautomerism of 2-phenacyl-1H-benzimidazoles and their
hydrogen bromide salts, Chem. Heterocycl. Comp. 47 (2011) 953-963
[15]
M. S. Frasinyuk, N. V. Gorbulenko, V. P. Khilya, Chemistry of the
heteroanalogs of isoflavones. 20. Benzimidazole analogs of isoflavones, Chem.
Heterocycl. Comp., 33 (1997) 1078-1085
[16]
E. Kolehmainen, B. Ośmiałowski, T. M. Krygowski, R. Kauppinen, M.
Nissinen, R. Gawinecki, Substituent and temperature controlled tautomerism:
multinuclear magnetic resonance, X-ray, and theoretical studies on 2-
phenacylquinolines, J. Chem. Soc., Perkin Trans. 2 (2000) 1259-1266
[17]
E. Kolehmainen, B. Ośmiałowski, M. Nissinen, R. Kauppinen, R. Gawinecki,
Substituent and temperature controlled tautomerism of 2-phenacylpyridine: the
hydrogen bond as a configurational lock of (Z )-2-(2-hydroxy-2-phenylvinyl)pyridine,
J. Chem. Soc., Perkin Trans. 2 (2000) 2185-2191
[18]
B. Ośmiałowski, E. Kolehmainen, M. Nissinen, T. M. Krygowski, R.
Gawinecki, (1Z,3Z)-1,4-Di(pyridin-2-yl)buta-1,3-diene-2,3-diol: The Planar Highly
Conjugated Symmetrical Enediol with Multiple Intramolecular Hydrogen Bonds, J.
Org. Chem. 67 (2002) 3339-3345
[19]
B. Ośmiałowski, E. Kolehmainen, R. Gawinecki, Identity Double-Proton
Transfer in (3Z)-3-Hydroxy-1,4-di(quinolin-2-yl)but-3-en-2-one, Chem. Eur. J. 9
(2003) 2710-2716
[20]
O. Martiskainen, R. Gawinecki, B. Ośmiałowski, K. Pihlaja, Electron
ionization mass spectra and tautomerism of 2-phenacylpyridines, Eur. J. Mass
Spectrom. 12 (2006) 25-30
[21]
R. Gawinecki, E. Kolehmainen, H. Loghmani-Khouzani, B. Ośmiałowski, T.
Lovász, P. Rosa, Effect of π-Electron Delocalization on Tautomeric Equilibria –
Benzoannulated 2-Phenacylpyridines, Eur. J.Org. Chem. (2006) 2817-2824
[22]
dihydro-2-benzoylmethylenequinolines:
unmethylated congeners, J. Mol. Struct. 525 (2000) 233-239
[23] M. M. Muir, O. Cox, L. A. Rivera, M. E. Cadiz, E. Medina, Synthesis and
R. Gawinecki, B. Ośmiałowski, E. Kolehmainen, M. Nissinen, N-methyl-1,2-
configurational dissimilarity with
characterization of new platinum(II) complexes containing thiazole and imidazole
donors III. Dichlorobis(styrylbenzazole)platinum(II) complexes, Inorg. Chim. Acta
191 (1992) 131-139

15
ACCEPTED MANUSCRIPT
[24]
R. J. Bartlett, Coupled-cluster approach to molecular structure and spectra: a
step toward predictive quantum chemistry, J. Phys. Chem. 93 (1989) 1697-1708
[25]
R. Ditchfield, W. J. Hehre, J. A. Pople, Self‐Consistent Molecular‐Orbital
Methods. IX. An Extended Gaussian‐Type Basis for Molecular‐Orbital Studies of
Organic Molecules, J. Chem. Phys. 54 (1971) 724-728
[26]
T. H. Dunning, Gaussian basis sets for use in correlated molecular calculations.
I. The atoms boron through neon and hydrogen, J. Chem. Phys., 90 (1989) 1007-1023
[27]
P. Charisiadis , V. G. Kontogianni, C. G. Tsiafoulis, A. G. Tzakos, M. Siskos,
1
I. P. Gerothanassi, H-NMR as a Structural and Analytical Tool of Intra- and
Intermolecular Hydrogen Bonds of Phenol-Containing Natural Products and Model
Compounds, Molecules 19 (2014) 13643-13682
[28]
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M.
Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R.
Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J.
Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö.
Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian 09, Revision
A.1, Gaussian, Inc., Wallingford CT, USA, 2009
[29]
Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment,
Release 2017, San Diego: Dassault Systèmes, 2016
[30]
F. N. Stepanov, S. L. Dawydowa, Heterocyclic derivatives of methylketones,
Zh. Obshch. Khim. 28 (1958) 891-896
1
[31]
R. A. More O’Ferrall, B. A. Murray,
H and 13C NMR spectra of α-
heterocyclic ketones and assignment of keto, enol and enaminone tautomeric
structures, J. Chem. Soc., Perkin Trans. 2 (1994) 2461-2470
[32]
C. Hansch, A. Leo, R. W. Taft, A survey of Hammett substituent constants and
resonance and field parameters, Chem. Rev. 91 (1991) 165-195

16
ACCEPTED MANUSCRIPT
[33]
J. D. Bene, I. Shavitt, The quest for reliability in calculated properties of
hydrogen-bonded complexes, in: S. Scheiner (Ed.), Molecular Interactions,
Chichester, UK, 1997, pp.157-179
[34]
Y. Dimitrova, S. Peyerimhof, Ab initio study of structures of hydrogen-bonded
nitric acid complexes, Chem. Phys. 254 (2000) 125-134
[35]
G. R. Desiraju, T. Steiner, The Weak Hydrogen Bond: In Structural Chemistry
and Biology, Oxford University Press, Oxford 1999
[36]
Oxford (1997)
[37] G. Gilli, F. Belluci, V. Ferretti, V. Bertolasi, Evidence for resonance-assisted
G. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press,
hydrogen bonding from crystal-structure correlations on the enol form of the .beta.-
diketone fragment, J. Am. Chem. Soc. 111 (1989) 1023-1028
[38]
V. Bertolasi, P. Gilli, V. Ferretti, G. Gilli, Evidence for resonance-assisted
hydrogen bonding. 2. Intercorrelation between crystal structure and spectroscopic
parameters in eight intramolecularly hydrogen bonded 1,3-diaryl-1,3-propanedione
enols, J. Am. Chem. Soc. 113 (1991) 4917-4925
[39]
P. Gilli, V. Bertolasi, V. Ferretti, G. Gilli, Evidence for resonance-assisted
hydrogen bonding. 4. Covalent nature of the strong homonuclear hydrogen bond.
Study of the O-H--O system by crystal structure correlation methods, J. Am. Chem.
Soc. 116 (1994) 909-915
[40]
V. Bertolasi, P. Gilli, V. Ferretti, G. Gilli, Resonance-Assisted O-H···O
Hydrogen Bonding: Its Role in the Crystalline Self-Recognition of β-Diketone Enols
and its Structural and IR Characterization, Chem.-Eur. J. 2 (1996) 925-934

ACCEPTED MANUSCRIPT
Highlights
• Synthesis of 1-metyhyl-2phenacylbenzimidazoles are presented
• Compounds are characterized using NMR and quantum-chemical calculations
• 1-Methyl-2-phenacylbenzimidazoles (ketimine) are in chloroform solutions in
equilibrium with their enolimine form
• Type of the substituents plays a significant role in tautomeric equilibrium