Synthesis, NMR, X-ray crystallography and DFT studies of some regioisomers possessing imidazole heterocycles

Article abstract of DOI:10.1016/j.molstruc.2021.130811

Imidazole-containing heterocycles: Imidazopyridines, imidazopyrimidines can exist in several tautomeric forms. Their regioselectivities were determined for N-alkylations with 4-chlorobenzyl bromide under basic conditions (K₂CO₃) in DMF. We observed that, regioisomers were mainly formed as a mixture in this reaction and N-benzylation occurs at a higher ratio on six membered heterocycles. Their structural assignments were made with the use of two-dimensional ¹H–¹H NOE (Nuclear Overhauser Effect Spectroscopy, NOESY) and ¹H-¹⁵N HMBC (Heteronuclear Multiple Bond Correlation) spectra. Further confirmation of the structure of 2c and 3c were obtained from X-ray crystallography. Experimental data was confirmed by Density Functional Theory (DFT) studies as well.

Full text of DOI:10.1016/j.molstruc.2021.130811

Journal of Molecular Structure 1243 (2021) 130811
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, NMR, X-ray crystallography and DFT studies of some
regioisomers possessing imidazole heterocycles
Mustafa Orhan Puskullua, Fatima Dogancb, Seckin Ozdenc, Ertan Sahind, Ismail Celika,
Hakan Gokerb,∗
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Lokman Hekim University, Ankara, Turkey
d Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Imidazole-containing heterocycles: Imidazopyridines, imidazopyrimidines can exist in several tautomeric
forms. Their regioselectivities were determined for N-alkylations with 4-chlorobenzyl bromide under ba-
sic conditions (K2CO3) in DMF. We observed that, regioisomers were mainly formed as a mixture in this
reaction and N-benzylation occurs at a higher ratio on six membered heterocycles. Their structural assign-
ments were made with the use of two-dimensional 1H–1H NOE (Nuclear Overhauser Effect Spectroscopy,
NOESY) and 1H-15 N HMBC (Heteronuclear Multiple Bond Correlation) spectra. Further confirmation of the
structure of 2c and 3c were obtained from X-ray crystallography. Experimental data was confirmed by
Density Functional Theory (DFT) studies as well.
Received 10 May 2021
Revised 27 May 2021
Accepted 28 May 2021
Available online 2 June 2021
Keywords:
Imidazo[4,5-b]pyridine
Imidazo[4,5-d]pyrimidine
Regioisomer
© 2021 Elsevier B.V. All rights reserved.
NOESY
1H-15 N HMBC
DFT
tomers of purine derivatives are mainly N7-H and N9-H species,
1. Introduction
probably due to their lower energy. Existence of this tautomerism,
Imidazopyridines and imidazopyrimidines (Purine) are formed
by fusing imidazole ring with pyridine and pyrimidine moieties,
respectively. These heterocycles have various isomeric forms like
imidazo[4,5-c]pyridines (a), imidazo[4,5-b]pyridines (b), 9H-purine
(c), 3H-purine (d) and 1H-purine (e) (Fig. 1).
in these bicyclic heterocycles has been shown with spectral data,
mainly nuclear magnetic resonance (NMR) spectroscopy. This mi-
gration is disappeared when the imidazole hydrogen is replaced
by alkyl groups. In our previous studies [2–4], we reported the
synthesis of some regioisomers of these cores and their struc-
tural assignments were achieved by selective synthesis and/or 2D-
NMR techniques. In continuation of these works, here we are ad-
dressing the reaction of some 2-(4-fluorophenyl)imidazopyridines
and/or 2-(4-fluorophenyl)imidazopyrimidines with 4-chlorobenzyl
bromide. Some 2D-NMR techniques including 1H-15N HMBC ex-
periment were used for the structural elucidation of regioisomeric
products obtained in these reactions. Further confirmation of two
compounds were obtained from X-ray crystallography.
Imidazopyridines are attractive hetereocycles for medicinal
chemists as their derivatives have been shown to exhibit several
biological activities. In 2017, a review was reported about pharma-
cological profiles of imidazopyridines such as anti-tumoral, anti-
microbial, anti-inflammatory, anti-diabetic, anti-hypertensive and
other pharmacological properties [1]. The NH group present in im-
idazopyridines is strongly acidic and weakly basic. This group ex-
hibits fast prototrophic tautomerism, which leads to equilibrium
mixtures. On the other hand, purines play a significant role in liv-
ing systems. They are basic component of nucleic acids and many
commercially used antiviral and antitumor drugs are derivatives
of naturally occurring purine bases (adenine and guanine). Vari-
ous tautomers of purine bases usually coexist due to the pres-
ence of several nitrogen sites in the molecule. The preferred tau-
2. Results and discussion
Targeted compounds were prepared using the methods out-
lined in Scheme 1-2. Cyclization of related (o-diamino)pyridine
and pyrimidine derivatives with sodium metabisulfite adduct
of 4-fluorobenzaldehyde gave required imidazo[4,5-c]pyridines 1,
imidazo[4,5-b]pyridines 2, imidazo[4,5-d]pyrimidines 3. The re-
gioselective alkylation of one within other nitrogen atoms is dif-
∗
Corresponding author.
E-mail addresses: goker@ankara.edu.tr, Hakan.Goker@ankara.edu.tr (H. Goker).
https://doi.org/10.1016/j.molstruc.2021.130811
0022-2860/© 2021 Elsevier B.V. All rights reserved.

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
Fig. 1. Some isomeric forms of imidazopyridines and imidazopyrimidines.
Scheme 1. Synthesis of 2-(4-fluorophenyl)imidazopyridine analogues.
ficult, in many cases and giving rise to mixtures of the regioiso-
mers. We reported the N-alkylation reaction of some imidazo[4,5-
b]pyridines in our previous studies [3,4]. It was declared that for-
mation ratio of the regioisomers could be changed with reaction
conditions and solvent effects. We aimed to explain some con-
flict resolutions on the formation of regioisomers. In the litera-
ture, there were two different results about the regioisomer for-
mation ratio under same conditions. Short literature review were
given on this topic in our previous article [4]. In this study, we
have prepared a series of some new 4-fluorophenylimidazo[4,5-
c]pyridine (1a) and 4-fluorophenylimidazo[4,5-b]pyridine (2a-c)
and 4-fluorophenylimidazo[4,5-d]pyrimidine (3a-c). Targeted com-
pounds 1–3 were prepared by condensation of the correspond-
ing pyrido or pyrimido o-diamines with Na2S2O5 adduct of 4-
fluorobenzaldehydes in DMF (Scheme 1-2). When we attempted
alkylation of 1 with 4-chlorobenzyl bromide under basic condi-
tions (K2CO3, DMF), alkylation were formed almost totally only
N-5 position with high yield (1a) as previously reported. Very
–
strong NOE interactions were seen between N CH2 and H-4,6 in
the NOESY spectra of 1a. These results were also confirmed by
HMBC correlations (Fig. 2). In contrast, under same conditions,
4-chlorobenzylation of compound 2 afforded the mixture of re-
gioisomers 2a (N-3) and 2b (N-4) within the yield of 5.5% and
33%, respectively. 2c (N-1) which is the expected 3rd regioiso-
mer were not detected in LC-MS chromatogram. This is why,
we have prepared 2c by selective regioisomer synthesis method,
between the reaction II and sodium metabisulfite adduct of 4-
fluorobenzaldehyde (Scheme-1). Characterisation of the individual
isomeric products was determined by observation of 2D-NOESY en-
–
hancements between the N CH2 and H-5,7 protons. In the NOESY
spectra of 2a, there were no NOE contours between benzylic
protons and pyridine protons, correlations were seen only be-
2

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
Scheme 2. Synthesis of 8-(4-fluorophenyl)purine analogues.
Alkylation of purines usually results with the formation of N-9
and N-7 alkylpurines and frequently N-9 regioisomer is formed as
major product. In similar conditions, we achieved the same result
with our previous studies and compound 3c (31%) was obtained as
N-1 regioisomer (Scheme-2). In addition, N-3 regioisomer 3b (6.5%)
was also isolated in our conditions; N-3 regioisomers of purines
are scarcely reported [4]. In this study, we have isolated N-9 re-
gioisomer as 3a with 1.2% yield. In NOESY spectrum of 3a, there
was no correlation between the benzylic CH2 and pyrimidine pro-
ꢀ
ꢀ
tons (H-2,6) as expected, interaction was possible with only H-2 ,6
ꢀꢀ ꢀꢀ
and H-2 ,6 . In contrast, in the NOESY spectra of 3b and 3c, while
ꢀ
ꢀ
–
no cross peaks were available between N CH2 and H-2 ,6 , but very
–
strong NOE interactions were detected between the N CH2 and H-
2,6.
On the other hand, in the last quarter, 1H-15N heteronuclear
multiple-bond correlation (HMBC) experiment was frequently used
for measurements of 15N chemical shifts and 1H-15N coupling con-
stants [5]. The chemical shifts of 15N nuclei are sensitive indica-
tors for structural analysis of biomacromolecules (nucleic acids,
nucleosides, nucleotides, proteins), alkaloids, purine-based antitu-
mor and antiviral drugs and many other organic products. How-
ever direct observation of 15N in NMR needs high quantity of sam-
ple, because of its low natural abundance (0.37%). At the same
time, its NMR sensitivity is very low as well. These difficulties can
be partially overcomed by using 2D-inverse detected NMR tech-
niques. In particular, 1H-15N HMBC experiment has been frequently
used for measurements of 15N chemical shifts and 1H-15N cou-
pling constants. These parameters are many times employed in
structural studies such as tautomerism, protonation, complexation,
N-alkylation and N-oxidation processes. Here are the some refer-
ences report that long-range 1H-15N HMBC measurements have
been used to differentiate the mixture of some regioisomers [6-
11]. We also report here the application of the 1H-15N HMBC ex-
periments as a useful tool for regioisomer differentiation. In the
1H-15N gHMBC spectrum of 2a (Fig. 3), long-range coupling of the
benzylic hydrogens to the N3 pyrrole-like nitrogen atom resonance
at δ 153 ppm was observed. N1 pyridine-like nitrogen atom (δ
Fig. 2. 1H-15 N HMBC spectra of compound 1a (CD3OD).
ꢀ
ꢀ
tween benzylic and H-2 and/or H-6 as expected. Strong corre-
lations were observed between benzylic and H-5 protons in the
spectrum of 2b. Similarly, cross peaks were observed between
–
N CH2 and H-7 proton in the spectrum of 2c. Complementary
structural information was provided by 2D-HMBC spectra of the
regioisomers.
It was possible to determine the chemical shift values of C-3a
and C-7a, by their correlations with pyridine hydrogens in HMBC
spectra. Subsequently, it could be available to determine other pos-
–
–
sible correlations (whether N CH2: C-3a or N CH2: C-7a) in sepa-
ration of regioisomers. The results obtained from the HMBC spectra
of 1a, 2(a-c) and 3(a-c) provided all expected correlations. Purine
is generally represented when a hydrogen atom is attached to N-9
and it is called N(9)H tautomer. It is obvious that structures may be
considered in which the proton is attached to the other nitrogens
of the molecule, yielding the tautomers N(7)H; N(3)H and N(l)H.
3

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
Fig. 4. 1H-15 N HMBC spectra of compounds 3b (CDCl3) and 3c (CD3OD).
CH2 and H-6,7 protons with N1 pyrrole-like nitrogen atom res-
onating at δ 147.6 ppm was observed. N4 pyridine nitrogen atom
(292.8 ppm) was coupled with protons H-5,6,7 of the pyridine ring.
1H-15N gHMBC experiment is more decisive for the separation of
the purine regioisomers. This is the best way to determine which
pyrimidine protons are H-2 or H-6.
In the 1H-15N gHMBC spectrum of 3b (Fig. 4), H-2 and benzylic
CH2 protons showed HMBC correlations with N3 resonating in δ
173.2 ppm. N1 pyrimidine nitrogen atom δ 260.4 ppm was coupled
with protons H-2,6 of the pyrimidine ring. In case of the second
regioisomer 3c (Fig. 4), strong HMBC correlations have been ob-
served between H-2,6, benzylic CH2 protons and N1 δ 179.3 ppm.
N3 pyrimidine nitrogen atom δ 259.6 ppm was coupled with pro-
tons H-2. All 1H-15N HMBC correlations also confirmed the pro-
posed structures of the all regioisomers. Complete analysis of the
1H and 13C NMR spectra of the synthesized compounds was pre-
sented by the aid of 1D and 2D NMR techniques such as COSY,
NOESY, gHSQC and gHMBC.
Fig. 3. 1H-15 N HMBC spectra of compounds 2a (CDCl3), 2b (DMSO–d6) and 2c
(DMSO–d6).
241.3 ppm) was correlated with H-6 of the pyridine ring. N4 pyri-
dine nitrogen atom (δ 267.3 ppm) was strongly correlated with
protons H-5,6. Because of the higher π-electron density, pyrrole-
like nitrogen atoms are substantially more shielded compared to
their pyridine-like counterparts (ca 50–100 ppm), our findings also
were in good agreement with the literature data [9,10].
Further confirmation of the structure of 2c and 3c were ob-
tained from X-ray crystallography. Their suitable crystals were
grown from CHCl3 solution. The structure of 2c was solved in
the monoclinic space group P21/c with four molecules in the
unit cell (Fig. 5). It has imidazopyridine core with substituted
4-fluorophenyl and 4-chlorobenzyl units. Imidazopyridine ring is
In case of the second regioisomer (2b) (Fig. 3), the discrimina-
ꢀꢀ ꢀꢀ
tory correlations between the benzylic CH2 protons, H-5,6,7,2 ,6
and N4 nitrogen atom of 1,2-dihydropyridine moiety were observed
ꢀ
ꢀ
at δ 174.3 ppm. Correlations were seen from H-5,2 ,6 to N3 at δ
completely planar. C C bonds in the pyridine ring are very close to
–
225.7 ppm. The interactions between the H-6,2 ,6 and N1 were ob-
served with less intensive contours at 240.1 ppm. For the third re-
gioisomer (2c) (Fig. 3), long-range coupling between the benzylic
each other (in the range of 1.373–1.399 A), C N bond lengths are
ꢀ
ꢀ
˚
–
˚
˚
also approximately equal (N1-C1 1.339 A, N1-C2 1.338 A). These
can be attributed to the presence electron delocalization in the
4

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
Fig. 5. Up) Molecular structure of 2c with the short contact geometry less than
the sum of vdW radius. Down) Layered stacking and short contact geometry of the
molecule 2c viewed down along the diagonal [011] axis.
Fig. 6. Up) Molecular structure of 3c with the short contact geometry (less than
–
the sum of vdW radius). Down) C H••• π and π-π stacking interactions of the
molecule 3c with the unit cell viewed down along the a-axis.
pyridine ring. In the imidazol unit, the single and double bonds
˚
are more clearly separated than each other (N2-C6 1.316 A, N2-C1
3. Geometric optimization, frontier molecular orbital, and
molecular electrostatic potentials analysis
˚
1.378 A). The dihedral angle between the C7/C12 and the C14/C19
aromatic plane is 58.7°. Dihedral angles between these rings and
imidazopyridine plane are 45.4° and 74.2°, respectively. Deviation
from planarity of the molecule is due to significant steric effects
and intermolecular interactions. The crystal structure is also stabi-
In terms of computational studies, it is important to estimate
the 3D structure of a compound and to calculate the bond length
and angle in atoms. Prediction of the lowest energy structure of
the compound is mainly used in organic and medicinal chem-
istry in many areas such as molecular docking, molecular dynamics
simulations, quantitative structure-activity relationship, and theo-
retical ADME calculations [12,13]. Accordingly, the optimized geo-
metric structures of the synthesized resulting products were de-
termined and shown in Figs. 7 and 8. Frontier molecular or-
˚
lized by the intramolecular C8-H8•••F1 [D•••A = 3.122(3) A] and
˚
C19-H19•••N1 [D•••A = 3.353(3) A] interactions. The π-π stack-
ing interactions between the delocalized π-electrons of the phenyl
rings are weak. The distance between the rings centroids are in the
˚
range of 3.96–5.64 A.
Structure of 3c was also solved in the monoclinic space group
P21/c (Fig. 6). It has imidazopyrimidine core with substituted 4-
fluorophenyl and 4-chlorobenzyl units. Purine ring is almost in
the same plane as the 4-fluorophenyl group. The dihedral an-
gle between the chlorophenyl and purine mean planes is 85.2°.
bital analysis of the compounds was performed. Gap ꢀE: (ELUMO
-
EHOMO), IP (-HOMO): ionization potential, EA (-LUMO): electron
affinity, X (IP+EA)/2: electronegativity, η (IP−EA/)2: chemical hard-
ness, S (1/2ἠ): chemical softness, μ −(IP+EA)/2: chemical poten-
tial, ω (μ2/2η): electrophilic index values were calculated. The
HOMO value is a measure of the electron-donating capacity of the
molecule, that is a parameter indicating the nucleophilicity of the
molecule. LUMO, on the other hand, is a measure of the elec-
tron withdrawal capacity, which expresses the electrophilicity of
the molecule. As shown in Figs. 7 and 8, the HOMO and LUMO
orbitals of all the compounds were localized on the imidazopy-
Here, purine heterocycle has 1H-purine (e) isomeric forms (Fig. 1).
˚
=
C
N double bonds in the ring are as follows; N4=C11 1.328(3) A,
˚
˚
N3=C12 1.335(3) A and N2=C8 1.302 A. Meanwhile, intermolecular
˚
˚
C7-H•••N1 [D•••A = 3.437(3) A], C9-H•••N4 [D•••A = 3.493(3) A]
˚
–
and C H•••π (4.0 A) interactions have a contribution in the for-
mation of a stable structure. The π-π stacking distances are in the
˚
range of 3.53–5.97 A.
5

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
Fig. 7. Optimized structures (left), molecular electrostatic potential (MEP) of highest-occupied molecular orbital (HOMO) - lowest-unoccupied molecular orbital (LUMO)
diagram (right) of the compounds 1a, 2a, 2b and 2c.
ridine/pyrimidine ring and the phenyl ring at the 2nd position.
HOMO orbitals C1-C2-C6 of the benzene atom in 2nd position and
C3-C4-C5 are localized on ternary atoms at their positions. They
are localized on the first three atoms of the imidazo structure and
three atoms of the pyridine/pyrimidine structures adjacent to them
and two adjacent carbon atoms. LUMO is localized on the C2-C3
and C5-C6 atoms of the benzene ring attached to the imidazo ring
at the 2nd position. Specific LUMO orbitals are localized on the
carbon at the 2nd position of the imidazo ring and the carbon of
the benzene ring attached to it. LUMO orbitals were formed on the
first carbon atom of the substituted benzene atom from nitrogen
atoms attached to the imidazo, pyridine or pyrimidine ring.
energy, also called ionization potential, is the amount of energy re-
quired to remove an electron from an isolated atom or molecule.
Electron affinity reflects an atom’s ability to accept an electron. It
shows the energy change that occurs when an electron is added to
a gaseous atom. Electronegativity, which expresses numerically the
tendency of an atom to attract electrons in a molecule, is a semi-
qualitative quantity. Chemical hardness is a measure of the stabil-
ity of the molecule and substances with high chemical hardness
do not polarize easily and react more difficulty. Chemical softness
is an approach that expresses the molecule is easier to polarize
and react to. The chemical potential reflects the ease with which
an electron is delivered from the system in its ground state. The
electrophilic index is another measure of the electron-donating ca-
pacity [14,15].
The gap value is also a value that numerically gives the electron
transition state of the molecule in HOMO to LUMO and this value
is a measure of the chemical stability of the compound. Ionization
6

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
Fig. 8. Optimized structures (left), molecular electrostatic potential (MEP) of highest-occupied molecular orbital (HOMO) - lowest-unoccupied molecular orbital (LUMO)
diagram (right) of the compounds 3a, 3b and 3c.
Table 1
Quantum parameters of imidazole-containing heterocycles compound 1a, 2a, 2b, 2c, 3a, 3b and 3c.
Comp.
LUMO
HOMO
Gap ꢀE
IP
EA
X
η
S
μ
ω
1a
2a
2b
2c
3a
3b
3c
−1,755
−1,630
−2,093
−1,699
−1,870
−2,314
−2,054
−5,935
−6,421
−5,984
−6,372
−6,762
−6,262
−6,129
4,180
4,790
3,890
4,673
4,892
3,948
4,074
5,935
6,421
5,984
6,372
6,762
6,262
6,129
1,755
1,630
2,093
1,699
1,870
2,314
2,054
3,845
4,026
4,039
4,036
4,316
4,288
4,092
2,090
2,395
1,945
2,337
2,446
1,974
2,037
0,239
0,209
0,257
0,214
0,204
0,253
0,245
−3,845
−4,026
−4,039
−4,036
−4,316
−4,288
−4,092
3,538
3,383
4,192
3,485
3,808
4,657
4,109
Gap ꢀE: (ELUMO-EHOMO), IP (-HOMO): Ionization potential, EA (-LUMO): Electron affinity, X (IP+EA)/2: Electroneg-
ativity, η (IP−EA/)2: Chemical hardness, S (1/2ἠ): chemical softness, μ −(IP+EA)/2: Chemical potential, ω (μ2
/2η): Electrophilic index.
As given in Table 1, 3b has the highest LUMO energy, electron
4. Conclusions
affinity, chemical softness and electrophilic index amongst all com-
pounds. On the other hand, compound 3a has the highest HOMO
energy, gap, ionization potential, electronegativity, chemical hard-
ness and chemical potential. The fact that the chlorobenzyl group
is in the 3rd and 9th positions carries the quantum parameters of
the compound to the highest and lowest levels.
It was found that N-benzylation of imidazo[4,5-c]pyridine,
imidazo[4,5-b]pyridine and imidazo[4,5-d]pyrimidine (Purine)
favourably was realized on the six membered N-heterocycles in
presence of anhydrous K2CO3 in DMF. Because of the very similar
polarities of imidazole N-alkylated products, they cannot be easily
separated from each other’s by column chromatography. However,
it is possible to separate N-alkylated six membered regioisomers
from the imidazole N-alkylated regioisomers. In our experiments,
imidazole N-alkylated regioisomers were obtained firstly from
the column chromatography. NOESY experiment is the primary
method for structural elucidation of these types of regioisomers.
The MEP plot is used to qualitatively understand the 3D elec-
tronic properties and charges of a compound through colors. In
this plot, the red areas are the regions of high electron density,
the blue areas are low electron density regions, yellow areas less
electron and green indicates neutral regions [16]. As shown in
Figs. 7 and 8, the electron density around the nitrogen atoms of
the imidazole ring is high. The status of the red regions varies de-
pending on the substitution of imidazole, pyridine, or pyrimidine
nitrogens. The benzene in the 2nd position and the variable benzyl
group are the neutral regions. The electron density of the aliphatic
hydrogens of the benzyl group is the least.
–
The cross peaks of N CH2 (at around 5–6 δ ppm) and aromatic
protons confirm their spatial proximity as an evidence for which
nitrogen atom is substituted. 1H–13C and 1H-15N HMBC tech-
niques can be an effective alternative method for assignment of
regioisomers. The complete structure elucidation of all synthesized
7

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
compounds was performed using 1D and 2D NMR experiments
including COSY, NOESY, gHSQC, gHMBC and XRD data.
5.1.3. 3-[(4-Chlorobenzylidene)amino]pyridine-2-amine (I)
To a suspension of 2,3-diaminopyridine (0.36 g, 3.3 mmol)
˚
4 A) and 4-
in THF (33 mL), dried molecular sieves (2 g,
5. Material and method
chlorobenzaldehyde (0.55 g, 3.9 mmol) were added. After refluxing
for 4 h, the mixture was stirred overnight. The reaction mixture
was filtered and concentrated, the residue was purified by silica
gel column chromatography and eluted with n-Hexane: EtOAc (70:
30) to (30–70) gradient, mp: 141–143 °C, lit.[20] 143°C, yield 0.55 g,
72.4%. 1H NMR (CDCl3) δ ppm: 5.3 (br.s, 2H, N H2), 6.59 (dd, 1H,
J = 5.6 & 5.2 Hz, H-5), 7.17 (d, 1H, J = 8 Hz, H-4), 7.37 (d, 2H,
5.1. Chemistry
Uncorrected melting points were measured on an Büchi B-540
capillary melting point apparatus. 1H (400 and 500 MHz) and
13C (100 and 125 MHz) NMR spectra were recorded employing
a Varian Mercury (AGILENT) 400 MHz and BRUKER AVANCE NEO
500 MHz FT spectrometers, chemical shifts (δ) are in ppm rela-
tive to TMS. The samples (5–15 mg) were prepared in 0.75 ml of
DMSO–d6, CDCl3 and CD3OD. TMS was used as an internal stan-
dard. The liquid chromatography mass spectrometry (LC-MS) spec-
tra were taken on a Waters Micromass ZQ connected with Wa-
ters Alliance HPLC (Waters Corporation, Milford, MA, USA), using
the ESI(+) method with a C-18 column (XTerra®, 4.6 × 250 mm,
5 μm).
ꢀ
ꢀ
ꢀ ꢀ
J = 8 Hz, H-3 ,5 ), 7.76 (d, 2H, H-2 ,6 ), 7.95 (d, 1H, J = 8 Hz, H-6),
8.38 (s, 1H, N CH); 13C NMR (CDCl3) δ ppm: 157.5, 154.9, 146.6,
=
137.4, 134.5, 131.6, 129.9, 129.1, 123.3, 113.8; MS (ESI+) m/z: 232
(M + H, 100%), 234 (M + H, 34%), C12H10ClN3.
5.1.4. N3-(4-Chlorobenzyl)pyridine-2,3-diamine (II)
Compound
I (0.5 g, 2.15 mmol) was dissolved in ethanol
(30 mL) and treated with sodium borohydride (0.6 g, 15.86 mmol).
After refluxing for 8 h, water was added and a light yellow
coloured powder was filtered, dried and crystallised from used
EtOAc: n-Hexane; yield 0.45 g, 90%, mp: 136–138°C. 1H NMR
5.1.1. Synthesis of sodium metabisulfite adduct of
–
–
4-fluorobenzaldehyde
(CDCl3) δ ppm: 3.62 (br.t, 1H, N H CH2), 4.22–4.27 (m, 4H, NH C
4-Fluorobenzaldehyde (7.5 mmol) was dissolved in EtOH
(25 mL) and sodium metabisulfite (0.8 g) (in 5 mL of water) was
added in portions. The reaction mixture was stirred vigorously and
more EtOH was added. The mixture was kept in a refrigerator for
a while. The white precipitate, the obtained salts were gained by
filtration, dried and used for the further steps without purification
and characterization.
H2 & 2-N H2), 6.65 (dd, 1H, J = 7.6 & 5.2 Hz, H-5), 6.74 (dd, 1H,
ꢀ
ꢀ ꢀ ꢀ
J = 7.6 & 1.2 Hz, H-4), 7.28–7.33 (m, 4H, H-2 ,6 ,3 ,5 ), 7.61 (dd, 1H,
J = 5.2 & 1.6 Hz, H-6); 13C NMR (CDCl3) δ ppm: 148.8, 137.2, 137.0,
133.2, 131.5, 128.88, 128.83, 117.6, 115.85, 47.5; MS (ESI+) m/z: 234
(M + H, 100%), 236 (M + H, 34%), C12H12ClN3.
5.1.5. General synthesis of 1a, 2a-b, 3a-c
K2CO3 (0.138 g, 1 mmol) was added to a suspension of the
1–3 (0.7 mmol) in DMF (0.5 mL) and stirred. One hour later,
4-chlorobenzyl bromide (0.12 g, 0.75 mmol) was added. After
overnight stirring at room temperature, water was added and pre-
cipitate was filtered.
5.1.2. General synthesis of 1, 2, 3
The mixture of sodium metabisulfite adduct of 4-
fluorobenzaldehyde (1 mmol) and corresponding 2,3-diamine
pyridine or 4,5-diaminopyrimidine (1 mmol), in DMF (2 mL) were
heated at 120°C, for 3–4 h. The reaction mixture was cooled,
poured into water. The resulting precipitate was collected by
filtration and boiled in EtOH filtered and dried.
5.1.5.1. 5-(4-Chlorobenzyl)−2-(4-fluorophenyl)−5H-imidazo[4,5-
c]pyridine (1a). Prepared from 1 (0.15 g) as described in general
method. Crude product was purified column chromatography by
using CH2Cl2: MeOH (95: 5), white solid, yield 0.130 g, 55%, mp:
229–232°C. 1H NMR δ ꢀppm (CD3OD): 5.65 (s, 2H, benzylic C H2),
5.1.2.1. 2-(4-Fluorophenyl)−5H-imidazo[4,5-c]pyridine (1). Prepared
from 3,4-diaminopyridine (0.11 g) as described in general method.
Yield 0.16 g, 75%, mp>275°C. 1H NMR δ ppm (DMSO–d6): 7.43–
ꢀ
ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ
7.2–7.26 (m, 2H, H-3 ,5 ), 7.36–7.41 (m, 4H, H-2 ,6 ,3 ,5 ), 7.76 (d,
ꢀ
ꢀ
7.48 (m, 2H, H-3 ,5 ), 7.69 (d, 1H, J = 5.6 Hz, H-7), 8.29–8.33 (m,
1H, J = 6.8 Hz, H-7), 8.13 (dd, 1H, J = 6.8 & 1.6 Hz, H-6), 8.32–8.36
ꢀ
ꢀ
ꢀ ꢀ
[H-6: H-4 (secondary)], [H-2 ,6 : H-3 ,5 ]; NOESY: [Benzylic C H2:
2H, H-2 ,6 ), 8.36 (d, 1H, J = 5.6 Hz, H-6), 9.03 (s, 1H, H-4); 13C
(m, 2H, H-2 ,6 ), 8.87 (d, 1H, J = 1.6 Hz, H-4); COSY: [H-6: H-7],
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
NMR (DMSO–d6): 163.6 (d, J = 247 Hz, C-4 ), 153.7, 143.4, 139.9,
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
138.5, 137.8, 129.5 (d, J = 9 Hz, C-2 ,6 ), 125.85 (d, J = 3.2 Hz, C-
H-4 / H-6 / H-2 ,6 ]; 13C NMR, HSQC & HMBC (CD3OD): 171.85
ꢀ
ꢀ
ꢀ
ꢀ
1 ), 116.2 (d, J = 22 Hz, C-3 ,5 ), 109.3; MS (ESI+) m/z: 214 (M + H,
(C-2), 165.6 (d, J = 247.5 Hz, C-4 ), 156.8 (C-7a), 146.0 (C-3a),
100%), C12H8FN3. (HCl salt avaliable in lit.[17 ]).
136.1 (C-4 ), 135.6 (C-1 ), 133.5 (C-6H), 132.7 (C-4H), 131.4 (d,
ꢀꢀ
ꢀꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
J = 8.4 Hz, C-2 ,6 H), 131.33 (d, J = 3 Hz, C-1 ), 130.8 (C-2 ,6 H),
ꢀꢀ ꢀꢀ
ꢀ ꢀ
5.1.2.2. 2-(4-Fluorophenyl)−3H-imidazo[4,5-b]pyridine (2). Prepared
from 2,3-diaminopyridine (0.11 g) as described in general method.
Yield 0.195 g, 91%, mp: 288–290°C, lit.[18 ] 289–290°C. 1H NMR δ
ppm (DMSO–d6): 7.25 (dd, 1H, J = 7.6 & 4.8 Hz, H-6), 7.4–7.45
130.5(C-3 ,5 H), 116.6 (d, J = 22 Hz, C-3 ,5 H), 113.75 (C-7H),
62.9 (Benzylic CH2); 1H-15N HMBC (CD3OD): [N5 (179.5 δ ppm) /
H-4,6,7 & benzylic CH2], [N1 (230.9 δ ppm) / H-6]; MS (ESI+) m/z:
338 (M + H, 100%), 340 (M + H + 2, 32%), 124 (M + H, 85%), 126
(M + H + 2, 28%), C19 H13ClFN3.
ꢀ
ꢀ
(m, 2H, H-3 ,5 ), 8.02 (br.d, 1H, J = 6.8 Hz, H-7), 8.29–8.32 (m,
ꢀ
ꢀ
2H, H-2 ,6 ), 8.36 (br.d, 1H, J = 3.6 Hz, H-5), 13.5 (br.s, NH); 13C
ꢀ
NMR (DMSO–d6): 163.4 (d, J = 247 Hz, C-4 ), 151.7, 143.7, 129.0
5.1.5.2. 3-(4-Chlorobenzyl)−2-(4-fluorophenyl)−3H-imidazo[4,5-
b]pyridine (2a) and 4-(4-Chlorobenzyl)−2-(4-fluorophenyl)−4H-
imidazo[4,5-b]pyridine (2b). Prepared from 2 (0.15 g) as described
in general method. Purification [CH2Cl2: MeOH (100: 4)] of the
crude powder first afforded 2a as white a solid, yield 0.013 g, 5.5%,
mp: 157–160°C. 1H NMR (CDCl3) δ ppm: 5.54 (s, 2H, benzylic C
ꢀ
ꢀ
ꢀ
(d, J = 8.9 Hz, C-2 ,6 ), 126.22 (d, J = 3 Hz, C-1 ), 117.95, 115.9 (d,
ꢀ
ꢀ
J = 22 Hz, C-3 ,5 ); MS (ESI+) m/z: 214 (M + H, 100%), C12H8FN3.
(NMR data are consistent with lit.[19 ]).
5.1.2.3. 8-(4-Fluorophenyl)−9H-purine (3). Prepared from 4,5-
diaminopyrimidine (0.11 g) as described in general method. Yield
0.155 g, 72%, mp: 325–326°C. 1H NMR δ ppm (DMSO–d6): 7.41–
ꢀꢀ ꢀꢀ
ꢀ ꢀ
H2), 7.02 (d, 2H, J = 8 Hz, H-2 ,6 ), 7.14–7.18 (m, 2H, H-3 ,5 ),
ꢀꢀ ꢀꢀ
7.24 (d, 2H, J = 8 Hz, H-3 ,5 ), 7.3 (dd, 1H, J = 4.8 & 8 Hz, H-6),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
7.45 (m, 2H, H-3 ,5 ), 8.27–8.31 (m, 2H, H-2 ,6 ), 8.87 (s, 1H, H-6),
7.62–7.66 (m, 2H, H-2 ,6 ), 8.1 (dd, 1H, J = 6.8 & 1.2 Hz, H-7),
8.41 (dd, 1H, J = 8 & 1.2 Hz, H-5); COSY: [H-6: H-5], [H-6: H-7],
9.1 (s, 1H, H-2); 13C NMR (DMSO–d6): 163.8 (d, J = 249 Hz, C-4 ),
ꢀ
ꢀ
ꢀ
ꢀ ꢀ ꢀ ꢀ ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ
[H-2 ,6 : H-3 ,5 ], [H-2 ,6 : H-3 ,5 ]; NOESY: [Benzylic C H2:
152.0, 129.7 (d, J = 8.9 Hz, C-2 ,6 ), 125.5, 116.2 (d, J = 22 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
H-2 ,6 / H-2 ,6 ]; 13C NMR, HSQC & HMBC (CDCl3) δ ppm: 164
C-3 ,5 ); MS (ESI+) m/z: 215 (M + H, 100%), C11 H7FN4.
8

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
ꢀ
13C NMR, HSQC & HMBC δ ppm (CDCl3): 170.8 (C-8), 164.8 (d,
J = 250 Hz, C-4 ), 156.2 (C-4), 142.6 (C-5), 142.5 (C-6H), 139.15 (C-
(d, J = 251 Hz, C-4 ), 153.7 (C-2), 148.7 (C-3a), 144.5 (C-5H), 135.1
ꢀꢀ
ꢀꢀ
ꢀ ꢀ
ꢀ
(C-1 ), 134.8 (C-7a), 133.75 (C-4 ), 131.2 (d, J = 8 Hz, C-2 ,6 H),
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀ ꢀ
129.1 (C-3 ,5 H), 127.9 (C-2 ,6 H), 127.4 (C-7H), 125.8 (d, J = 3 Hz,
2H), 135.6 (C-4 ), 131.9 (C-1 ), 130.9 (d, J = 9 Hz, CH-2 ,6 ), 130.2
ꢀ
ꢀ ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀ
C-1 ), 119.15 (C-6H), 116.1 (d, J = 22 Hz, C-3 ,5 H), 46.2 (benzylic
carbon); 1H-15 N HMBC (CDCl3): [N3 (153 δ ppm): benzylic CH2],
[N1 (241.3 δ ppm): H-6], [N4 (267.3 δ ppm): H-5 / H-6]; MS (ESI+)
m/z: 338 (M + H, 100%), 340 (M + H + 2, 32%), 124 (M + H,
100%), 126 (M + H + 2, 32%), C19 H13ClFN3.
(C-2 ,6 H), 129.6 (C-3 ,5 H), 129.4 (d, J = 3 Hz, C-1 ), 115.7 (d,
ꢀ
ꢀ
J = 22 Hz, C-3 ,5 H), 53.7 (N CH2); 1H- 15N HMBC (CDCl3): [N3
(173.2 δ ppm): H-2 / benzylic CH2], [N1 (260.4 δ ppm): H-2 / H-
6]; MS (ESI+) m/z: 339 (M + H, 100%), 341 (M + H + 2, 32%), 124
(M + H, 95%), 126 (M + H + 2, 32%), C18 H12ClFN4.
–
Continued elution CH2Cl2: MeOH (100: 4) provided 2b as a
white solid, yield 0.09 g, 33%, mp: 128–130°C. 1H NMR (DMSO–d6)
δ ppm: 5.90 (s, 2H, benzylic C H2), 7.22 (dd, 1H, J = 7.2 & 6 Hz, H-
Continued elution with (CH2Cl2: MeOH 100: 4) provided 3c,
yield 0.0735 g, 31%, mp: 269–272°C. 1H NMR δ ppm (CD3OD):
ꢀ
ꢀ
–
5.67 (s, 2H, N CH2), 7.21–7.6 (m, 2H, H-3 ,5 ), 7.44 (s, 4H, H-
ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
6), 7.29–7.34 (m, 2H, H-3 ,5 ), 7.42 (d, 2H, J = 8.4 Hz, H-3 ,5 ), 7.57
2 ,6 ,3 ,5 ), 8.35–8.37 (m, 2H, H-2 ,6 ), 8.85 (d, 1H, J = 2 Hz, H-
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
ꢀ ꢀ
(d, 2H, J = 8.4 Hz, H-2 ,6 ), 8.23 (d, 1H, J = 8 Hz, H-7), 8.31 (d, 1H,
6), 8.97 (d, 1H, J = 2 Hz, H-2); COSY: [H-2 ,6 : H-3 ,5 ], [H-2: H-
ꢀ
ꢀ
6 (secondary)]; NOESY: [N CH2: H-2 / H-6 / H-2 ,6 ]; 13C NMR
ꢀꢀ ꢀꢀ
J = 5.6 Hz, H-5), 8.4–8.44 (m, 2H, H-2 ,6 ); COSY: [H-6: H-5], [H-6:
–
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
H-7], [H-2 ,6 : H-3 ,5 ], [H-2 ,6 : H-3 ,5 ]; NOESY: [Benzylic C H2:
& HSQC & HMBC δ ppm (CD3OD): 174.6 (C-8), 167.1 (C-4), 166.2
H-5 / H-2 ,6 ]; 13C NMR, HSQC & HMBC (DMSO–d6) δ ppm: 166.9
ꢀꢀ ꢀꢀ
ꢀ
ꢀꢀ
(d, J = 248 Hz, C-4 ), 145.8 (C-2H), 138.0 (C-5), 136.45 (C-4 ),
ꢀ
ꢀꢀ
ꢀ
ꢀ
(C-2), 163.2 (d, J = 245 Hz, C-4 ), 153.6 (C-3a), 145.0 (C-7a), 134.7
135.05 (C-1 ), 134.2 (C-6H), 131.8 (d, J = 9 Hz, C-2 ,6 H), 131.1
ꢀꢀ
ꢀꢀ
ꢀ
ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ
ꢀ
(C-1 ), 133.1 (C-4 ), 131.2 (C-5H), 131.1 (d, J = 2.6 Hz, C-1 ), 130.3
and 130.6 (C-2 ,3 ,5 ,6 ), 130. 9 (d, J = 3.2 Hz, C-1 ), 116.7 (d,
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
J = 22.5 Hz, CH-3 ,5 ), 59.9 (N CH2); 1H-15 N HMBC (CD3OD): [N1
(179.3 δ ppm): H-2,6 / benzylic CH2], [N3 (259.6 δ ppm): H-2]; MS
(ESI+) m/z: 339 (M + H, 100%), 341 (M + H + 2, 30%), 124 (M + H,
74%), 126 (M + H + 2, 24%), C18 H12ClFN4.
ꢀ
ꢀ
(C-2 ,6 H), 129.7 (d, J = 9 Hz, C-2 ,6 H), 128.7 (C-3 ,5 H), 127.9
–
ꢀ
ꢀ
(C-7H), 115.5 (d, J = 21 Hz, C-3 ,5 H), 113.2 (C-6H), 55.1 (benzylic
carbon); 1H-15N HMBC (DMSO–d6): [N4 (174.3 δ ppm): H-7 / H-6 /
H-5 / H-2 ,6 / benzylic C H2], [N3 (225.7 δ ppm): H-5 / H-2 ,6 ],
ꢀꢀ ꢀꢀ
ꢀ ꢀ
[N1 (240.1 δ ppm): H-6 / H-2 ,6 ]; MS (ESI+) m/z: 338 (M + H,
100%), 340 (M + H + 2, 32%), 124 (M + H, 85%), 126 (M + H + 2,
28%), C19 H13ClFN3.
ꢀ
ꢀ
5.2. DFT/B3LYP calculations
The quantum chemical calculations of imidazole-containing
heterocycles compounds were performed by choosing DFT, the
Becke-3–Lee-Yang-Parr (B3LYP) 6–311 G (d,p) basis set with Gaus-
sian 09 package software [21,22]. Optimization of compounds
was done to find the most stable structure with minimal energy
and molecular electrostatic potentials (MEP) were calculated. Elec-
tronic parameters were measured like HOMO-LUMO energies (ꢀE
(ELUMO−EHOMO), ionization potential (IP = −HOMO), electron affin-
ity (EA = −LUMO), electronegativity (X = [IP+EA]/2), chemical
hardness (ἠ = [IP−EA]/2), chemical softness (S = 1/2ἠ), chemical
potential (μ = −[IP+EA]/2) and electrophilic index (ω = μ2/2η).
The DFT results were evaluated and visualized via the GaussView
6.0 program [23].
5.1.5.3. 1-(4-Chlorobenzyl)−2-(4-fluorophenyl)−1H-imidazo[4,5-
b]pyridine (2c). A mixture of II (0.233 g, 1 mmol) and Na2S2O5
adduct of 4-fluorobenzaldehyde (0.228 g, 1 mmol) in DMF (0.4 mL)
was heated at 120°C for 4 h. Water was added, the resulting pre-
cipitate was filtered and dried. Precipitate was crystallised from
CHCl3: n-Hexane as colourless crystals, yield 0.25 g, 73.7%, mp:
202–204°C. 1H NMR (DMSO–d6) δꢀꢀ ppꢀꢀm: 5.63 (s, 2H, benzylic C
H2), 7.02 (d, 2H, J = 8.4 Hz, H-2 ,6 ), 7.27 (dd, 1H, J = 7.8 &
ꢀꢀ ꢀꢀ
4 Hz, H-6), 7.34 (d, 2H, J = 8.4 Hz, H-3 ,5 ), 7.37–7.40 (m, 2H,
ꢀ
ꢀ
ꢀ ꢀ
H-3 ,5 ), 7.80–7.83 (m, 2H, H-2 ,6 ), 7.94 (dd, 1H, J = 8 & 1.2 Hz,
H-7), 8.46 (dd, 1H, J = 4.8 & 1.2 Hz, H-5); COSY: [H-6: H-5], [H-6:
H-7], [H-2 ,6 : H-3 ,5 ], [H-2 ,6 : H-3 ,5 ]; NOESY: [N1-C H2: H-7
/ H-2 ,6 / H-2 ,6 ]; 13C NMR, HSQC & HMBC (DMSO–d6) δ ppm:
ꢀ
ꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀ
163.1 (d, J = 248 Hz, C-4 ), 155.0 (C-3a), 154.3 (C-2), 144.6 (C-5H),
5.3. Crystallography
ꢀꢀ
ꢀꢀ
ꢀ ꢀ
135.3 (C-1 ), 132.2 (C-4 ), 131.4 (d, J = 8.3 Hz, C-2 ,6 H), 128.7
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
(C-3 ,5 H), 128.1 (C-7a), 128.1 (C-2 ,6 H), 125.8 (d, J = 3.2 Hz,
For the crystal structure determination, single-crystal of the
compound 2c and 3c was used for data collection on a four-
circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-
ꢀ
ꢀ ꢀ
C-1 ), 119.2 (C-7H), 118.1 (C-6H), 115.8 (d, J = 22 Hz, C-3 ,5 H),
46.9 (benzylic carbon); 1H-15N HMBC (DMSO–d6): [N1 (147.6 δ
ppm): H-6 / H-7 / benzylic CH2], [N4 (292.8 δ ppm): H-5 / H-6 /
H-7]; MS (ESI+) m/z: 338 (M + H, 100%), 340 (M + H + 2, 32%),
124 (M + H, 85%), 126 (M + H + 2, 28%), C19 H13ClFN3.
dimensional area IP detector). Graphite-monochromated Mo-K
˚
α
radiation (λ = 0.71073 A) and oscillation scans technique with
ꢀw = 5° for one image were used for data collection. The lat-
tice parameters were determined by the least-squares methods on
the basis of all reflections with F2>2σ (F2). Integration of the in-
tensities, correction for Lorentz and polarization effects and cell
refinement were performed using CrystalClear (Rigaku/MSC Inc.,
2005) software [24]. The structure was solved by direct methods
using SHELXS-97 [25] and non-hydrogen atoms were refined using
anisotropic displacement parameters by full-matrix least-squares
procedure using the program SHELXL-97 [25]. H atoms were po-
sitioned geometrically and refined using a riding model. The fi-
nal difference Fourier maps showed no peaks of chemical signifi-
cance. Crystal data for 2c: C19 H13N3FCl, crystal system, space group:
monoclinic, P21/c; (no:14); unit cell dimensions: a = 10.047(3),
5.1.5.4. 9-(4-Chlorobenzyl)−8-(4-fluorophenyl)−9H-purine
(3a),
3-(4-Chlorobenzyl)−8-(4-fluorophenyl)−3H-purine (3b) and 1-(4-
Chlorobenzyl)−8-(4-fluorophenyl)−1H-purine (3c). Prepared from 3
(0.15 g) as described in general method. Crude solid (0.166 g) pow-
der was purified by column chromatography. Purification (EtOAc:
n-Hexane 40: 60) first afforded the compound 3a, yield 0.004 g,
1
–
ꢀꢀ ꢀꢀ
1.7%. H NMR δ ppm (CD3OD): 5.64 (s, 2H, N CH2), 7.01–7.04
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
(m, 2H, H-2 ,6 ), 7.25–7.32 (m, 4H, H-,3 ,5 ,3 ,5 ), 7.73–7.77 (m,
ꢀ
ꢀ
ꢀ ꢀ
2H, H-2 ,6 ), 8.98 (s, 1H, H-6), 9.13 (s, 1H, H-2); COSY: [H-2 ,6 :
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
–
H-3 ,5 ], [H-2 ,6 : H-3 ,5 ]; NOESY: [N CH2: H-2 ,6 / H-2 ,6 ];
MS (ESI+) m/z: 339 (M + H, 100%), 341 (M + H + 2, 34%), 124
(M + H, 91%), 126 (M + H + 2, 30%), C18 H12ClFN4.
˚
b = 10.319(3), c = 15.844(5) A, α = 90, β = 105.00(8), γ = 90°;
3
3
˚
Continued elution with (EtOAc: n-Hexane 55: 45) provided 3b,
as white powder, yield 0.015 g, 6.5%, mp: 165–167°C. 1H NMR δ
volume; 1586.7(8) A , Z = 4; calculated density: 1.414 g/cm ; ab-
sorption coefficient: 0.256mm−1; F(000): 696; θ-range for data
collection 2.1–28.4°; refinement method: full matrix least-square
on F2; data/parameters: 3946/218; goodness-of-fit on F2: 1.141; fi-
nal R-indices [I > 2σ(I)]: R1 = 0.055, wR2 = 0.168, largest diff. peak
ꢀ
ꢀ
–
ppm (CDCl3): 5.77 (s, 2H, N CH2), 7.17–7.21 (m, 2H, H-3 ,5 ), 7.37
ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ
(d, 2H, J = 8.4 Hz, H-3 ,5 ), 7.46 (d, 2H, J = 8.4 Hz, H-2 ,6 ), 8.42
ꢀ
ꢀ
(s, 1H, H-2), 8.5–8.53 (m, 2H, H-2 ,6 ), 8.9 (s, 1H, H-6); COSY: [H-
ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ ꢀꢀ
ꢀ
ꢀ
ꢀ ꢀ
˚
–
2 ,6 : H-3 ,5 ], [H-2 ,6 : H-3 ,5 ]; NOESY: [N CH2: H-2 / H-2 ,6 ];
and hole: 0.533 and −0.525 e A−3. Crystal data for 3c: C18 H12N4FCl,
9

M.O. Puskullu, F. Doganc, S. Ozden et al.
Journal of Molecular Structure 1243 (2021) 130811
crystal system, space group: triclinic, P21/c; (no:14); unit cell di-
[6] P.A. McDonnell, A.D. Gauthier, M.P. Ferro, Differentiation of Regioisomers at 15 N
natural abundance using gradient-enhanced 1H/15 N HMBC NMR spectroscopy,
Magn. Reson. Chem. 36 (1998) 35–38, doi:10.1002/(SICI)1097-458X(199801)36:
1ꢁ35::AID-OMR208ꢂ3.0.CO;2-A.
˚
mensions: a = 6.4899(3), b = 18.1279(9), c = 13.4756(7) A, α = 90,
3
˚
β = 102.039(1), γ = 90°; volume; 1550.51(9) A , Z = 4; calcu-
lated density: 1.451 g/cm3; absorption coefficient: 0.264 mm−1
;
[7] M. Corredor, J. Bujons, A. Messeguer, I. Alfonso, 15 N NMR spectroscopic and
theoretical GIAO-DFT studies for the unambiguous characterization of disub-
stituted 1,2,3-triazoles, Org. Biomol. Chem. 11 (2013) 7318–7325, doi:10.1039/
C3OB41587B.
F(000): 696; θ-range for data collection 2.0–28.3°; refinement
method: full matrix least-square on F2; data/parameters: 3848/217;
goodness-of-fit on F2: 1.090; final R-indices [I > 2σ(I)]: R1 = 0.046,
[8] P.M. Chaudhary, S.R. Chavan, M. Kavitha, S.P. Maybhate, S.R. Deshpande,
A.P. Likhite, P.R. Rajamohanan, Structural elucidation of propargylated prod-
ucts of 3-substituted-1,2,4-triazole-5-thiols by NMR techniques, Magn. Reson.
Chem. 46 (2008) 1168–1174, doi:10.1002/mrc.2307.
[9] A. Salgado, C. Varela, A.M.G. Collazo, P. Pevarello, Differentiation between
[1,2,4]triazolo[1,5-a]pyrimidine and [1,2,4]triazolo[4,3-a]-pyrimidine regioiso-
mers by 1H-15 N HMBC experiments, Magn. Reson. Chem. 48 (2010) 614–622,
doi:10.1002/mrc.2634.
−3
˚
wR2 = 0.143; largest diff. peak and hole: 0.170 and −0.202 e A
.
CCDC-2062653 (2c) and CCDC-2062824 (3c) numbers contain
the supplementary crystallographic data for the structures. These
data are provided free of charge via the joint CCDC/FIZ Karlsruhe
deposition service www.ccdc.cam.ac.uk/structures.
[10] T.S. Saleh, A.E.M. Mekky, A.S. Al-Bogami, Convergent synthesis strategy of novel
fused azines: 1H-15 N HMBC NMR as a tool for assertion of the site selectivity
of Aza-Michael addition reaction, Curr. Org. Synth. 13 (2016) 278–290, doi:10.
2174/1570179412666150914201114.
Credit author statement
M.O. Puskullu, F. Doganc, S. Ozden: Synthesis and structure elu-
cidation, E. Sahin: Spectroscopy (XRD crystallography); I. Celik: Cal-
culations (DFT); H. Goker: Synthesis and structure elucidation, Su-
pervision
[11] U.D. Phalgune, K. Vanka, P.R. Rajamohanan, GIAO/DFT studies on 1,2,4-triazole-
5-thiones and their propargyl derivatives, Magn. Reson. Chem. 51 (2013) 767–
774, doi:10.1002/mrc.4012.
[12] M.C. Ford, P.S. Ho, Computational tools to model halogen bonds in medicinal
chemistry, J. Med. Chem. 59 (5) (2016) 1655–1670, doi:10.1021/acs.jmedchem.
5b00997.
[13] C. Bissantz, B. Kuhn, M. Stahl, A medicinal chemist’s guide to molecular inter-
actions, J. Med. Chem. 53 (14) (2010) 5061–5084, doi:10.1021/jm100112j.
[14] T.A. Ajayeoba, J.O. Woods, A.O. Ayeni, T.J. Ajayi, R.A. Akeem, E.C. Hosten,
O.F. Akinyele, Synthesis, crystallographic, computational and molecular docking
studies of new acetophenone-benzoylhydrazones, J. Mol. Struct. 1237 (2021)
130275, doi:10.1016/j.molstruc.2021.130275.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
[15] Y.S. Mary, Y.S. Mary, A.S. Rad, R. Yadav, I. Celik, S. Sarala, Theoretical investi-
gation on the reactive and interaction properties of sorafenib-DFT, AIM, spec-
troscopic and Hirshfeld analysis, docking and dynamics simulation, J. Mol. Liq.
330 (2021) 115652, doi:10.1016/j.molliq.2021.115652.
Acknowledgements
[16] S. Lahmidi, F. S¸ en, Y. Sert, F. Ucun, E.M. Essassi, J.T. Mague,
A research
Central Laboratory of Pharmacy, Faculty of Ankara University
provided support for acquisition of the NMR and mass spectrome-
ter used in this work.
on structural vibrational, surface characterization of 2-methyl-3-{5-methyl-
[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4H-pyrido[1,2-a]pyrimidin-4-one hydrate:
SCXRD, FT-IR, MEP, Hirshfeld and Molecular Docking studies, J. Mol. Struct.
1235 (2021) 130198, doi:10.1016/j.molstruc.2021.130198.
[17] D.W. Robertson, E.E. Beedle, J.H. Krushinski, G.D. Pollock, H. Wilson, V.L. Wyss,
J.S. Hayes, Structure-activity relationships of arylimidazopyridine cardioton-
ics: discovery and inotropic activity of 2-[2-methoxy-4-(methylsulfinyl)phenyl]-
1H-imidazo[4,5-c]pyridine, J. Med. Chem. 28 (1985) 717–727, doi:10.1021/
jm00383a006.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130811.
[18] J. Macdonald, V. Oldfield, V. Bavetsias, J. Blagg, Regioselective C2-arylation of
imidazo[4,5-b]pyridines, Org. Biomol. Chem. 11 (2013) 2335–2347, doi:10.1039/
C3OB27477B.
[19] L. Pan, N. Hang, C. Zhang, Y. Chen, S. Li, Y. Sun, Z. Li, X. Meng, Synthesis
and biological evaluation of novel benzimidazole derivatives and analogs tar-
geting the LRP3 inflammasome, Molecules 22 (2017) 213–228, doi:10.3390/
molecules22020213.
References
[1] M. Krause, H. Foks, K. Gobis, Pharmacological potential and synthetic ap-
proaches of imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine derivatives,
Molecules 22 (2017) 399–424, doi:10.3390/molecules22030399.
[2] F. Doganc, M. Alp, H. Goker, Separation and identification of the mix-
ture of 2-(3,4-dimethoxyphenyl)-1-n-propyl or (4-chlorobenzyl)-5 and (6)-1H-
benzimidazolecarbonitriles, Magn. Reson. Chem. 54 (2016) 851–857, doi:10.
1002/mrc.4463.
[20] P.K. Dubey, C.V. Ratnam Formation of heterocyclic rings containing nitro-
gen: part XXVI-condensation of pyridine 2,3-diamine with aromatic aldehydes,
Proc. Indian Acad. Sci. 85 (1977) 204–209, doi:10.1007/BF03049482.
[21] A.D. Beck, Density-functional thermochemistry. III. The role of exact exchange,
J. Chem. Phys. 98 (7) (1993) 5648-6, doi:10.1063/1.464913.
[22] C. Lee, W. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-energy
formula into a functional of the electron density, Physical Rev. B 37 (2) (1988)
785, doi:10.1103/PhysRevB.37.785.
[23] R. Dennington, T.A. Keith, J.M. Millam, GaussView V. 6, Semichem Inc, Shawnee
Mission, KS, 2016.
[24] Rigaku/MSC, Inc., 9009 New Trails Drive, The Woodlands, TX 77381.
[25] G.M. Sheldrick, A short history of SHELX, Acta Cryst. A 64 (2008) 112–122,
doi:10.1107/S0108767307043930.
[3] H.
Göker,
S.
Özden,
Regioselective
N-alkylation
of
2-(3,4-
dimethoxyphenyl)imidazo[4,5-b] and [4,5-c]pyridine oxide derivatives:
synthesis and structure elucidation by NMR, J. Mol. Struct. 1197 (2019)
183–195, doi:10.1016/j.molstruc.2019.07.058.
[4] C. Karaaslan, F. Doganc, M. Alp, A. Koc, A.Z. Karabay, H. Göker, Regioselective
N-alkylation of some imidazole-containing heterocycles and their in vitro anti-
cancer evaluation, J. Mol. Struct. 1205 (2020) 1–13, doi:10.1016/j.molstruc.2019.
127673.
[5] R. Marek, V. Sklenár, NMR studies of purines, Annu. Rep. NMR Spectrosc. 54
(2004) 201–242, doi:10.1016/S0066-4103(04)54005-X.
10