Synthesis, spectroscopic (FT-IR and UV-Vis), crystallographic and theoretical studies, and a molecular docking simulation of an imatinib-like template

Article abstract of DOI:10.1107/S2053229619015523

The aim of the present study was to report the crystal structure and spectroscopic, electronic, supramolecular and electrostatic properties of a new polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (C₉H₈N₄). The compound was synthesized under microwave irradiation. The single-crystal X-ray structure analysis revealed an angle of 13.36 (8)° between the planes of the rings, as well as molecules linked by Nsp ² - H?N hydrogen bonds forming dimers along the crystal. The material was analyzed by FT-IR vibrational spectroscopy, while a computational approach was used to elucidate the vibrational frequency couplings. The existence of Nsp ² - H?N hydrogen bonds in the crystal was confirmed spectroscopically by the IR peaks from the N - H stretching vibration shifting to lower wavenumbers in the solid state relative to those in the gas phase. The supramolecular studies confirmed the formation of centrosymmetric R 2 ²(8) rings, which correspond to the formation of dimers that stack parallel to the b direction. Other weak C - H?π interactions, essential for crystal growth, were found. The UV-Vis spectroscopic analysis showed a donor-acceptor process, where the amino group acts as a donor and the pyridine and pyrimidine rings act as acceptors. The reactive sites of the molecule were identified and their quantitative values were defined using the electrostatic potential model proposed in the multifunctional wave function analyzer multiwfn. The calculated interaction energies between pairs of molecules were used to visualize the electrostatic terms as the leading factors against the dispersion factors in the crystal-growth process. The docking results showed that the amino group of the pyrimidine moiety was simultaneously anchored by hydrogen-bonding interactions with the Asp427 and His407 protein residues. This compound could be key for the realization of a series of syntheses of molecules that could be used as possible inhibitors of chronic myelogenous leukemia.

Full text of DOI:10.1107/S2053229619015523

research papers
Synthesis, spectroscopic (FT–IR and UV–Vis),
crystallographic and theoretical studies, and a
molecular docking simulation of an imatinib-like
template
ISSN 2053-2296
Rodolfo Moreno-Fuquen,a* Kevin Arango-Daravina,a Esteban Garcia,a Juan-C.
˜
Tenoriob and Javier Ellenab
Received 1 September 2019
Accepted 17 November 2019
a
´
´
Grupo de Cristalografıa, Departamento de Quımica, Universidad del Valle, AA 25360, Santiago de Cali, Colombia, and
b
Edited by A. R. Kennedy, University of Strath-
clyde, Scotland
´
Instituto de Fısica de Sao Carlos, IFSC, Universidade de Sao Paulo, USP, Sao Carlos, SP, Brazil. *Correspondence e-mail:
˜
˜
˜
rodolfo.moreno@correounivalle.edu.co
Keywords: imatinib-like; crystal structure; mol-
ecular docking simulation; computational
chemistry; pyrimidinamine.
The aim of the present study was to report the crystal structure and
spectroscopic, electronic, supramolecular and electrostatic properties of a new
polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (C9H8N4). The compound was
synthesized under microwave irradiation. The single-crystal X-ray structure
analysis revealed an angle of 13.36 (8)ꢀ between the planes of the rings, as well
as molecules linked by Nsp2—Hꢁ ꢁ ꢁN hydrogen bonds forming dimers along the
crystal. The material was analyzed by FT–IR vibrational spectroscopy, while a
computational approach was used to elucidate the vibrational frequency
couplings. The existence of Nsp2—Hꢁ ꢁ ꢁN hydrogen bonds in the crystal was
confirmed spectroscopically by the IR peaks from the N—H stretching vibration
shifting to lower wavenumbers in the solid state relative to those in the gas
phase. The supramolecular studies confirmed the formation of centrosymmetric
R22(8) rings, which correspond to the formation of dimers that stack parallel to
the b direction. Other weak C—Hꢁ ꢁ ꢁꢀ interactions, essential for crystal growth,
were found. The UV–Vis spectroscopic analysis showed a donor–acceptor
process, where the amino group acts as a donor and the pyridine and pyrimidine
rings act as acceptors. The reactive sites of the molecule were identified and their
quantitative values were defined using the electrostatic potential model
proposed in the multifunctional wave function analyzer multiwfn. The calculated
interaction energies between pairs of molecules were used to visualize the
electrostatic terms as the leading factors against the dispersion factors in the
crystal-growth process. The docking results showed that the amino group of the
pyrimidine moiety was simultaneously anchored by hydrogen-bonding inter-
actions with the Asp427 and His407 protein residues. This compound could be
key for the realization of a series of syntheses of molecules that could be used as
possible inhibitors of chronic myelogenous leukemia.
CCDC reference: 1966319
Supporting information: this article has
supporting information at journals.iucr.org/c
1. Introduction
The pyrimidine system is a six-membered organic heterocycle
with N atoms at positions 1 and 3 of the ring (Brown, 2009;
Padwa et al., 1984). Pyrazine and pyridazine, other diazines,
have N atoms at different positions in the ring. Of the nucleic
acids, three nucleobases are pyrimidine derivatives, namely
pyrimidine-2,4(1H,3H)-dione (Zajac et al., 2003), 5-methyl-
pyrimidine-2,4(1H,3H)-dione (Joule & Mills, 2010) and
4-aminopyrimidin-2(1H)-one (Chahwan et al., 2010).
The presence of a pyrimidine skeleton in thymine, cytosine
and uracil, which are essential building blocks of DNA and
RNA nucleic acids, may be one of the reasons why pyrimidine
products are so widely used in therapeutic applications. This
work seeks to study a system that can include the character-
# 2019 International Union of Crystallography
Acta Cryst. (2019). C75, 1681–1689
https://doi.org/10.1107/S2053229619015523 1681

research papers
Table 1
Experimental details.
istics of pyrimidine and pyridine as a whole, i.e. 4-(pyridin-2-
yl)pyrimidin-2-amine (hereafter PPA). The presence of the
pyrimidine ring covalently bound to pyridine makes it a very
attractive scaffold for the synthesis of diverse products that
can exhibit very interesting biological and chemical properties.
The importance of the pyrimidine nucleus can be appreciated
since it is related to many vital molecules, such as thiamine
(Bettendorff et al., 1996, 2007), riboflavin (Zempleni et al.,
1996) and folic acid (Bailey & Ayling, 2009). In addition, the
pyrimidine skeleton is present in many synthetic compounds,
such as barbituric acid, and in compounds such as veranal,
which is used in hypnosis (Porter, 1979). Many pyrimidine
derivatives have antibacterial (Sharma et al., 2004), antifungal
(Agarwal et al., 2000), analgesic (Sondhi et al., 2008), anti-
inflammatory (Amir et al., 2007), antihypertensive (Rana et al.,
2004) or anticancer activities (Xie et al., 2009). In this work,
the structure of PPA (Scheme 1) was investigated using both
theoretical studies and X-ray crystallography.
Crystal data
Chemical formula
Mr
C9H8N4
172.19
Crystal system, space group
Temperature (K)
Monoclinic, I2/a
293
11.4608 (15), 5.3791 (9), 26.740 (4)
91.457 (12)
1647.9 (4)
8
Mo Kꢃ
0.09
0.40 ꢂ 0.23 ꢂ 0.20
˚
a, b, c (A)
ꢂ (ꢀ)
3
˚
V (A )
Z
Radiation type
ꢄ (mmꢄ1
Crystal size (mm)
)
Data collection
Diffractometer
Absorption correction
Tmin, Tmax
Bruker Enraf–Nonius KappaCCD
Gaussian (SADABS; Bruker, 2012)
0.624, 0.995
No. of measured, independent and
observed [I > 2ꢅ(I)] reflections
Rint
4441, 2379, 1688
0.020
0.703
ꢄ1
˚
(sin ꢆ/ꢇ)max (A
)
Refinement
R[F2 > 2ꢅ(F2)], wR(F2), S
No. of reflections
No. of parameters
0.046, 0.134, 1.03
2379
126
H-atom treatment
H atoms treated by a mixture of
independent and constrained
refinement
0.22, ꢄ0.22
ꢄ3
˚
Áꢈmax, Áꢈmin (e A
)
Computer programs: DATCOL (Bruker, 2006), EVALCCD (Duisenberg et al., 2003),
SHELXT (Sheldrick, 2015a), SHELXL2014 (Sheldrick, 2015b), ORTEP-3 (Farrugia,
2012), Mercury (Macrae et al., 2008) and CrystalExplorer (McKinnon et al., 2004).
2. Experimental
2.1. Structure and spectra
The reactions were monitored by thin-layer chromato-
graphy (TLC). The melting points were determined on a
7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H), 7.36 (dd,
J = 7.5, 4.8 Hz, 1H), 5.33 (s, 2H, NH2). 13C NMR (100 MHz,
chloroform-d): ꢁ 164.23, 163.29, 159.49, 154.48, 149.57, 137.07,
125.19, 121.61, 108.18. IR (FT–IR): 3469.94, 3296.35, 3136.61,
1651.07, 1614.42, 1566.20, 1544.98, 1463.97, 1431.18, 1342.46,
1301.95, 1242.16, 1211.30, 1103.28, 1093.64, 846.75, 804.32,
783.10, 742.59, 650.01.
¨
Buchi melting point B-450 apparatus. The IR spectra were
recorded on a Shimadzu IR Affinity-1 FT–IR coupled with a
Pike Miracle ATR. The NMR spectra were recorded on a
Bruker Avance 400 spectrometer operating at 400.13 MHz for
1H and 100.61 MHz for 13C, using chloroform-d as the solvent
and tetramethylsilane (TMS) as the internal standard.
Chemical shifts (ꢁ) are reported in ppm, coupling constants (J)
in Hertz (Hz) and classical abbreviations are used to describe
the signal multiplicities. The UV–Vis absorption spectrum of
PPA was obtained in acetonitrile solution at room tempera-
ture in the range 200–600 nm using a UV–Vis Shimadzu 1700
spectrophotometer. Chemicals and solvents were purchased
from Sigma–Aldrich and were used without further purifica-
tion.
2.2. Synthesis and crystallization
A mixture of enaminone 1 (1 equiv.), guanidine 2
(1.05 equiv.), sodium hydroxide (1.17 equiv.) and propanol
was subjected to microwave radiation at 150 W for 10 min at
95 ꢀC. The crude product obtained was extracted with ethyl
acetate (3 ꢂ 50 ml). TLC monitoring (Cl2CH2/MeOH,
40:1 v/v) revealed the presence of a unique product. Com-
pound 3 (grey colour) was finally obtained in a yield of 80.72%
(m.p. 140 ꢀC) (see Scheme 2).
2.3. Refinement
The collected crystal data and structure refinement details
of PPA are summarized in Table 1. H atoms on C atoms were
˚
placed in calculated positions (C—H = 0.93 A) and were
refined using a riding-model approximation, with Uiso(H) =
1.2Ueq(parent). The H atoms of the amine group were refined
isotropically.
1H NMR (400 MHz, chloroform-d): ꢁ 8.69 (dd, J = 4.7,
1.7 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 7.9 Hz, 1H),
ꢃ
1682 Moreno-Fuquen et al.
Analysis of an imatinib-like template
Acta Cryst. (2019). C75, 1681–1689

research papers
Table 2
Hydrogen-bond geometry (A, ).
ꢀ
˚
D—Hꢁ ꢁ ꢁA
D—H
Hꢁ ꢁ ꢁA
Dꢁ ꢁ ꢁA
D—Hꢁ ꢁ ꢁA
N4—H4Bꢁ ꢁ ꢁN1i
0.91 (2)
2.10 (2)
3.0154 (19)
175.8 (16)
Symmetry code: (i) ꢄx þ 1; ꢄy þ 2; ꢄz þ 1.
dynamics, transformations and molecular assembly properties.
It is therefore interesting to undertake a supramolecular study
of PPA to find the noncovalent relationships governing its
supramolecular structure (Turro, 2005). The noncovalent
bonds most frequently discussed in biological systems are
hydrogen bonds. Several properties observed in these systems
depend on interactions with neighbouring molecules. The
formation of dimers, rings or infinite chains of molecules,
generated by hydrogen bonds, affects the properties of these
biological systems. In this particular system, the formed N—
Hꢁ ꢁ ꢁN interactions are evocative of the interactions between
complementary DNA base pairs. Other weaker interactions,
such as N4—H4Aꢁ ꢁ ꢁC3, that complement crystalline forma-
tion, are also observed. The N4—H4B group acts as a
hydrogen-bond donor for atom N1i (Table 2), forming
hydrogen-bonding dimers with R22(8) graph-set motifs. These
rings afford dimers at the supramolecular level and each dimer
forms an approximate right angle with the next dimer as they
run along the [001] direction (Fig. 2). The formation of this
kind of dimer is characteristic of the crystal growth of pyri-
midine compounds. The crystal packing also features weak
C—Hꢁ ꢁ ꢁꢀ interactions. This weak attractive force may play an
important role in various fields of biology or chemistry
(Nakamura et al., 1982; Sakaki et al., 1993). The C8—H8 group
shows an interaction with the centroid of the pyridine ring in
Figure 1
The molecular structure of PPA, with displacement ellipsoids drawn at
the 50% probability level. H atoms are shown as spheres of arbitrary
radii.
2.4. Computational study
All theoretical calculations were performed on the system
in the gas phase using Becke’s three-parameter hybrid func-
tional (B3) (Becke, 1993) with the LYP correlation functional
(B3LYP) (Lee et al., 1988) and the 6-311G++(d,p) basis set.
The geometry optimization of the molecule was followed by
frequency calculations to prove that the energy minimum had
been found. The vibrational wavenumber assignments were
´
performed using the VEDA4 program (Jamroz, 2013) and the
vibrations were visualized with the aid of GaussView (Version
5.0.8; Nielsen & Holder, 2009).
3. Results and discussion
3.1. Single-crystal X-ray analysis
The amino group is anti with respect to the pyridine N3
atom. The N2—C4—C5—N3 torsion angle is ꢄ167.20 (12)ꢀ.
The planes of the rings of the PPA molecule form a dihedral
angle of 13.36 (8)ꢀ. All bond lengths, bond angles and inter-
molecular distances were found to be normal. The X-ray
diffraction analysis confirmed the proposed structure and is
depicted in Fig. 1.
1
the molecule with the symmetry code (ꢄx + 1, y ꢄ , ꢄz + 32),
2
with a distance from the H8 atom to the ring centroid of
˚
2.95 A.
3.2. Supramolecular features
3.3. Hirshfeld surfaces
The projection of the molecular structure, which is generally
related to atoms and covalent bonds, towards a level domi-
nated by noncovalent interactions should lead to the use of
new rules governing these supramolecular structures and their
Hydrogen-bond interactions enhance the stability of the
supramolecular structure and this behaviour can be explored
through Hirshfeld surface analysis using the CrystalExplorer
program (Spackman & Jayatilaka, 2009), which allows the
Figure 2
Partial crystal structure of PPA, showing the formation of dimers linked by N—Hꢁ ꢁ ꢁN hydrogen bonds, as well as chains of dimers linked by C—Hꢁ ꢁ ꢁCg
1
3
interactions (Cg is the centroid of the pyridine ring), running along [001]. [Symmetry codes: (i) ꢄx + 1, ꢄy + 2, ꢄz + 1; (ii) ꢄx + 1, y ꢄ , ꢄz + .]
2
2
ꢃ
Acta Cryst. (2019). C75, 1681–1689
Moreno-Fuquen et al.
Analysis of an imatinib-like template 1683

research papers
Figure 3
(a) dnorm surfaces displaying the pairwise Nꢁ ꢁ ꢁH interactions and the C—Hꢁ ꢁ ꢁCg interactions (Cg is the centroid of the pyridine ring). (b) Fingerprint
plot with the characteristic interactions circled, showing Nꢁ ꢁ ꢁH in black, Cꢁ ꢁ ꢁH in green and Hꢁ ꢁ ꢁH in red.
visualization of the different types of interactions within the
crystal structure, including Nꢁ ꢁ ꢁH and Cꢁ ꢁ ꢁH interactions.
Assigning de and di as the external and internal distances of an
atom to the Hirshfeld surface and normalizing these pairs of
values with respect to the van der Waals (vdW) radii of the
corresponding atoms results in the so-called dnorm surface.
Contacts smaller than the sum of the vdW radii of the two
atoms result in a negative value, and negative values are
highlighted on the surface in red. Contacts close to the limit of
the vdW radii are shown in white, and those contacts greater
than the sum of the vdW radii are highlighted on the surface in
blue (see Fig. 3a).
The Hirshfeld surface dnorm (in red) indicates the locations
of the strongest intermolecular contacts, e.g. the H4B and H7
atoms, which form the most important interactions in the
molecule (Fig. 3a). When mapping de and di on this surface,
these two values are associated, resulting in relations that are
24.2% of the total surface. The Cꢁ ꢁ ꢁH and Hꢁ ꢁ ꢁC interactions
combined, which appear as spikes and are indicated by green
circles, comprise 8.4% of the surface, and Hꢁ ꢁ ꢁH interactions,
indicated by red circles, comprise 45.3% of the Hirshfeld
surface. The results of the dnorm surface coincide with the
results of the fingerprint plot.
3.4. Molecular electrostatic potential (MEP)
The MEP is the potential that a positive charge unit would
experience at any point surrounding the molecule due to the
electron-density distribution in the molecule. The MEP was
used to clarify the interactions among PPA molecules, as well
as the most important reactive sites on the molecule that could
be used in later syntheses. Regions with high negative
potentials have a high probability of performing nucleophilic
attacks or undergoing protonation reactions, and such sites
were identified around the N1 and N3 atoms, which showed
MEPs equal to ꢄ32.409 and ꢄ25.890 kcal molꢄ1, respectively.
These regions could be responsible for the formation of
hydrogen bonds at the active site of the corresponding
receptor. The reactive sites of the title molecule were located
with the help of the Multifunctional Wavefunction Analyzer
(Lu & Chen, 2012). High positive potentials indicate regions
with low electron density and a high probability of being
attacked by a nucleophile. The positive regions in this mol-
ecule are around atoms H4A and H4B of the amino group,
with MEP values of 34.833 and 33.040 kcal molꢄ1, respectively
(Fig. 4). These electrostatic potential values can be used as
predictors of chemical reactivity. The pyrimidine group,
containing both proton-donating and proton-accepting sites,
enables dimerization by formation of hydrogen bonds in the
solid state, achieving N—Hꢁ ꢁ ꢁN hydrogen-bond distances that
are in the typical range of hydrogen bonds between amino-
pyrimidines. The values of the resulting electrostatic potentials
in this molecular system make it possible to predict the
formation of additional hydrogen bonds or the possible
formation of covalent bonds in a synthesis process (Sarcher et
al., 2014).
˚
combined in intervals of 0.01 A, providing the so-called
fingerprint. The Hirshfeld surface analysis for PPA shows that
the Nꢁ ꢁ ꢁH and Hꢁ ꢁ ꢁN interactions, which appeared as spikes
and are indicated by black circles (Fig. 3b), together comprise
Figure 4
3D representation of the electrostatic potential around the molecule.
ꢃ
1684 Moreno-Fuquen et al.
Analysis of an imatinib-like template
Acta Cryst. (2019). C75, 1681–1689

research papers
Table 3
Molecular pairs and interaction energies (kJ molꢄ1) obtained from the energy framework calculation for PPA.
Colour
N
Symmetry code
R
Electron density
Eele
Epol
Edis
Erep
Etot
i
ii
2
2
2
1
1
1
1
2
1
1
2
x, y, z
ꢄx + 12, y + 12, ꢄz + 12
5.36
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
HF/3–21G
ꢄ3.2
ꢄ3.4
ꢄ7.4
ꢄ7.5
ꢄ0.5
ꢄ2.8
ꢄ4.3
ꢄ10.7
2.7
ꢄ1.8
ꢄ1.4
ꢄ1.5
ꢄ1.6
ꢄ0.8
ꢄ1.2
ꢄ1.1
ꢄ2.4
ꢄ0.8
ꢄ22.4
ꢄ0.5
ꢄ35.3
ꢄ16.2
ꢄ12.1
ꢄ10.5
ꢄ8.9
17.8
12.6
5.8
4.8
5.0
8.7
2.4
17.3
1.0
ꢄ21.8
ꢄ8.7
7.54
6.88
8.07
10.36
6.66
7.56
5.82
9.55
9.39
8.82
iii
iv
v
vi
vii
viii
ix
x
x, ꢄy, z + 12
ꢄ14.7
ꢄ14.3
ꢄ5.0
ꢄx + 12, ꢄy + 12, ꢄz
ꢄx + 12, ꢄy + 12, ꢄz
ꢄx, ꢄy, ꢄz
ꢄ24.6
ꢄ7.9
ꢄ18.8
ꢄ10.3
ꢄ18.7
ꢄ1.0
ꢄx, y, ꢄz + 12
x, ꢄy, z + 12
ꢄ22.5
ꢄ4.5
ꢄx, y, ꢄz + 12
ꢄx, ꢄy, ꢄz
ꢄ73.5
ꢄ15.6
ꢄ5.5
62.1
2.5
ꢄ53.2
ꢄ7.3
xi
x, ꢄy, z + 12
ꢄ4.0
˚
Notes: scale factors used to determine Etot: Eele = 1.019, Epol = 0.651, Edis = 0.901 and Erep = 0.811. R is the distance between molecular centroids (A). The colour bar indicates the colour-
code interactive map for the first sphere of coordination around PPA.
Nucleophilic substitution reactions performed in our
research group followed an effective path involving the amino
functional group and resulted in the formation of new cova-
lent bonds by integrating different heterocyclic rings into the
reaction products. These compounds also show a trend in the
crystalline state towards the generation of dimers, showing the
formation of R22(8) synthons. A second polymorphic com-
pound of PPA, which crystallizes in the monoclinic space
group P21/c with eight molecules in the unit cell, is reported in
the literature (Bejan et al., 1996). In the asymmetric unit, a
dimerization by the formation of N—Hꢁ ꢁ ꢁN hydrogen bonds,
is observed. A study of the molecular electrostatic potential of
the second polymorph showed equivalent values in regions of
maximum and minimum potential that evidence the formation
of new N—Hꢁ ꢁ ꢁN interactions enhancing the formation of
trimers or tetramers with R22(8) rings along [100]. The induc-
tion of these new N—Hꢁ ꢁ ꢁN hydrogen bonds in a certain way
inhibits, in the polymorph molecules, under solvent-free
conditions, the creation of new relatively strong interactions,
thereby reducing their reactivity with respect to the title PPA
compound. In this way, the responsibility for suffering
nucleophilic attacks, under the conditions that were previously
established, must be focused on regions close to the pyridine N
atoms.
3.5. 3D energy framework analysis
A more realistic interpretation of the molecular interactions
in a crystalline compound can be achieved using the Crystal-
Explorer program, which was inspired by the ‘PIXEL’ model
of molecular interactions (Gavezzotti, 2005). Precise calcula-
tions, in which molecules are analyzed as a whole and not by
Figure 5
Energy frameworks corresponding to the different energy components, i.e. (a) electrostatic, (b) dispersion and (c) total energy framework, along the b
axis. The tube size (scale factor) used in all the energy frameworks was 200.
ꢃ
Acta Cryst. (2019). C75, 1681–1689
Moreno-Fuquen et al.
Analysis of an imatinib-like template 1685

research papers
Table 4
Vibrational assignments of PPA.
calculations based on atom–atom contacts, were used, and
these calculations considered interactions between pairs of
molecules, and the energy values can be described according
to Mackenzie et al. (2017) as the sum of the electrostatic (Ees),
polarization (Epol), dispersion (Edis) and exchange–repulsion
(Erep) terms.
6311G++(d,p)
(cmꢄ1
Calculated
Exp
FT–IR
)
Assignations (PED %)
(cmꢄ1
)
ꢊ NCCC (88)
ꢊ CNCN (74)
46
91
–
–
ꢂ CCN (70)
ꢊ CNCN (84)
ꢊ CNCN (78)
ꢉ CC (36) + ꢂ CCN (26)
ꢊ HNCN (90)
ꢂ NCN (63)
ꢊ CCCC (70)
ꢊ CNCN (56)
ꢂ CCN (42) + ꢊ HNCN (37)
ꢊ CCNC (63)
ꢊ HNCN (58) + ꢂ CCN (30)
ꢂ CNC (66)
ꢂ CCC (74)
ꢂ CNC (72)
ꢊ CCNC (62)
ꢊ HCCC (53) + ꢂ CNC (46) ꢊ CNCC (25) +
ꢂ CCN (18)
ꢊ HCCC (53) + ꢂ CNC (46) + ꢊ CNCC (25) +
ꢂ CCN (18)
142
190
232
317
334
360
415
444
485
504
524
603
639
665
694
764
–
–
–
–
–
–
–
–
–
–
–
–
650
–
–
783
Etot ¼ Ees þ Epol þ Edis þ Erep
The interaction energies for the selected molecular pairs in the
˚
first sphere of coordination (radius 3.8 A) around PPA are
presented in Table 3.
The values of the interaction energies calculated between
the pairs of molecules that appear in Table 4 and that are
visualized in Fig. 5 show that one of the interactions with Etot
=
ꢄ53.2 kJ molꢄ1 contributes 31% of the total energy value and
is related to pairs of molecules that are connected by N—
Hꢁ ꢁ ꢁN hydrogen bonds, and the distance R between their
˚
centroids is 9.39 A. These interactions are represented
predominantly by the term Ees, which is shown as the
maximum term of this characteristic among all the interactions
764
–
ꢊ CNCN (52) + ꢊ CNCC (16) + ꢊ HCCC (15)
ꢊ HCCN (43) + ꢊ CNCN (27) + ꢊ HCCC (10)
ꢊ HCCN (38) + ꢊ CCNC (12) + ꢊ HCNC (11) +
ꢊ CNCN (11)
ꢊ HCCC (79)
ꢉ NC (67)
811
825
877
804
–
847
present. A second important contribution to the total energy is
˚
ꢄ21.8 kJ molꢄ1, and this interaction is mainly represented by
the dispersion term (ꢄ35.3 kJ mol-1) and involves mainly ꢀ–ꢀ
interactions.
Energy framework diagrams help clarify the crystal packing
by combining efficient interactions with novel graphical
representations, facilitating the visualization of the supra-
molecular architecture of molecular structures. The global
process of energetic interactions among pairs of PPA mol-
ecules is shown in Fig. 5, and the important contributions of
the electrostatic term and the minor contribution of the
dispersion term to the Etot energy is shown. The results of the
energy framework diagrams, indicated by the cylinders, reveal
the directions of the interactions among the centroids of the
molecules and their relative strengths in the molecular
packing in different directions.
for pairs of related molecules with R = 5.36 A and Etot
=
929
945
989
–
926
–
–
995
–
–
–
1094
1103
–
ꢊ HCCC (70) + ꢊ CCCC (10)
ꢂ CCN (18) + ꢂ HCNC (41)
ꢂ CCN (13) + ꢂ HCNC (29)
ꢂ CCC (55) + ꢉ CC (21)
ꢊ HCCC (79) + ꢊ CNCC (11)
ꢂ HNC (34) + ꢂ CNC (13)
ꢉ CC (34) + ꢂ CCC (19) + ꢂ HCC (12)
ꢉ NC (24) + ꢂ HCN (17) + ꢂ HCC (13)
ꢂ CNC (22) + ꢂ HCC (22) + ꢉ CC (10)
ꢂ HCC (31) + ꢂ HNC (21) + ꢂ CNC (16)
ꢉ CC (15) + ꢂ HCC (57)
ꢉ NC (70)
ꢉ NC (49) + ꢉ NC (10)
ꢂ HCN (44) + ꢉ NC (17)
ꢂ HCN (20) + ꢉ CC (15) + ꢂ CCN (11)
ꢂ HCN (33) + ꢉ CC (12)
ꢂ HCC (42)
1008
1008
1014
1023
1043
1068
1112
1122
1155
1172
1257
1288
1319
1325
1369
1461
1469
1482
–
–
1211
1242
1302
–
1342
1431
–
ꢉ CC (21) + ꢂ HCC (15)
ꢉ CN (26) + ꢂ HCN (18) + ꢁ HNH (13) +
ꢂ CCN (13)
3.6. Vibrational analysis
1464
To determine the spectroscopic behaviour of PPA, vibra-
tional frequencies were calculated using the DFT/6-
311G++(d,p) basis set. The theoretical and experimental
Fourier transform IR (FT–IR) vibrational peaks are listed in
Table 4. The differences between the calculated and experi-
mental values are primarily due to the presence of inter-
molecular interactions, including the formation of hydrogen
bonds in the crystalline phase, and these interactions are not
observed in the gas phase.
ꢂ HCC (43) + ꢉ CC (16)
ꢉ CC (37)
ꢉ CC (53)
ꢉ CC (44) + ꢁ HNH (11)
ꢉ CC (36) + ꢁ HNH (13)
ꢁ HNH (34) + ꢉ NC (16)
ꢉ CH (95)
1508
1591
1612
1621
1629
1643
3145
3146
3173
3193
3220
3239
3608
3736
–
1545
1566
–
1614
1651
–
3057
3079
3137
–
ꢉ CH (91)
ꢉ
as CH (79) + ꢉs CH (18)
ꢉs CH (78) + ꢉas CH (17)
ꢉ CH (99)
ꢉ CH (95)
–
3296
3470
3.6.1. N—H vibrations. The N—H stretching vibration
appears in the region 3375 ꢅ 125 cmꢄ1 and the N—H defor-
mation vibrations are in the regions 1510–1500, 1400–1300 and
740–730 cmꢄ1 (Socrates, 1981; Roeges, 1994). For the title
molecule, potential energy distribution (PED) analysis gives
the N—H symmetric stretching at 3608 cmꢄ1, and the N—H
asymmetric stretch is observed at 3736 cmꢄ1. The experi-
ꢉs NH (100)
ꢉ
as NH (100)
Notes: ꢉ = stretching, ꢂ = in-plane bending, ꢁ = scissoring, ꢋ = out-of-plane bending, ꢊ =
torsion vibration, s = symmetric and as = asymmetric.
and the asymmetric N—H stretch is at 3470 cmꢄ1 (Fig. 3S in
the supporting information). Pyridin-2-amine shows an
experimental ꢉas N—H band at 3445 cmꢄ1(Buyukmurat et al.,
mental value for the symmetric stretching band is 3296 cmꢄ1
,
¨ ¨
ꢃ
1686 Moreno-Fuquen et al.
Analysis of an imatinib-like template
Acta Cryst. (2019). C75, 1681–1689

research papers
Table 5
Theoretical spectrum of the electronic absorption of PPA in the gas phase using TD-SCF B3LYP/6-311G++(d,p).
Transition
ꢇcalc (nm)
ꢇexp (nm)
Oscillator strength
EHOMO (a.u.)
ELUMO (a.u.)
EHOMO–LUMO gap (a.u.)
Energy gap (eV)
I
II
III
316
250
232
323
242
207
0.0964
0.3648
0.0295
ꢄ0.22922
ꢄ0.26322*
ꢄ0.26322*
ꢄ0.06586
ꢄ0.06586
ꢄ0.0344**
0.16336
0.19736
0.22881
4.4452
5.3704
6.2262
Notes: (*) HOMO-2; (**) LUMO-1.
1999; Mary et al., 2010). When comparing this value with the
calculated value of the studied molecule, a red shift is
observed (Athokpam et al., 2017), perhaps caused by the
formation of dimers involving N—Hꢁ ꢁ ꢁN hydrogen bonds
(Fig. 2). The existence of Nsp2—Hꢁ ꢁ ꢁN hydrogen bonds in the
PPA crystal was confirmed spectroscopically by its IR peaks
due to the N—H stretching vibration shifting to lower wave-
numbers in the solid state relative to those in the gas phase.
3.6.2. C C vibrations. The ring C C stretching vibrations
were in the region 1400–1600 cmꢄ1. In aromatic compounds
such as pyridines, the strongest band is usually at approxi-
mately 1500 cmꢄ1 and the pyridin-2-amine C C stretching
observed at 1211, 1242 and 1302 cmꢄ1. The DFT calculations
give the C—N stretching bands at 1257, 1288 and 1319 cmꢄ1
.
3.6.4. C—H vibrations. The existence of one or more
aromatic rings was confirmed by the C—H ring-related
vibrations. The C—H stretching occurs above 3000 cmꢄ1 and
appear as weak-to-moderate bands relative to the aliphatic
bands. The experimental C—H stretching vibrations are at
3057, 3079 and 3137 cmꢄ1, while the calculated values for the
title molecule are at 3146, 3173 and 3193 cmꢄ1. The calculated
and experimental vibrational frequencies are generally in
good agreement. No scaling factor for frequencies was used.
band is present at approximately 1428–1584 cmꢄ1 (Buyuk-
¨ ¨
3.7. UV–Vis analysis
murat et al., 1999). Density functional theory (DFT) calcula-
tions showed aromatic C C stretching modes in the 1469–
1629 cmꢄ1 region.
UV–Vis spectrophotometry, one of the most commonly
used techniques in pharmaceutical chemistry, is used to
determine the amount of UV or visible radiation absorbed by
a substance in solution or in the solid state. Analysis of the
frontier orbitals in a molecule may indicate how the molecule
interacts with other species. A molecule with a small HOMO–
LUMO energy gap (HOMO is the highest occupied molecular
orbital and LUMO is the lowest unoccupied molecular
orbital) is more polarizable and is generally more chemically
reactive or less kinetically stable (Fleming, 1976). The elec-
tronic transition energies were determined using time-
3.6.3. C—N vibrations. The experimental C—N stretching
band is at 1464 cmꢄ1. The PED analysis shows a stretching
band at 1482 cmꢄ1. In pyridin-2-amine (Mary et al., 2010), the
C—NH2 stretch occurs at 1325 cmꢄ1. The theoretical scis-
soring vibrations occur at 1621, 1629 and 1643 cmꢄ1, while the
experimental IR spectrum shows the scissoring vibrations at
1614 and 1651 cmꢄ1. The experimental values for pyridin-2-
amine indicates that the IR scissoring mode occurs at
1627 cmꢄ1. In turn, the C—N stretching vibrations are
Figure 6
(a) UV–Vis absorption spectrum of PPA. (b) The frontier orbitals obtained with TD-DFT/6-311++G(d,p) (isovalue = 0.05).
ꢃ
Acta Cryst. (2019). C75, 1681–1689
Moreno-Fuquen et al.
Analysis of an imatinib-like template 1687

research papers
molecule under study, EHOMO = ꢄ6.24 eV, ELUMO = ꢄ1.79 eV,
energy gap = 4.45 eV, I = 6.24 eV, A = 1.79 eV, global hardness
ꢌ = 2.27 eV, ꢄ = ꢄ4.02 eVand global electrophilicity = ꢄ2/2ꢌ =
3.56 eV. The comparison of the results obtained in the analysis
of the frontier orbitals with the results of the molecular
electrostatic potentials (MEP) contributes to revealing
possible properties of the molecule under study.
3.8. Molecular docking study
Since derivatives of the pyrimidine–pyridine fragment and
structurally related compounds are well known as Bcr-Abl
tyrosine kinase oncoprotein inhibitors, we decided to under-
take a molecular docking study of one of the precursors in this
series of inhibitors, PPA, into the binding site of the Bcr-Abl
oncogene. PDB ID 3gvu was retrieved from the PDB (http://
www.rcsb.org/pdb) for the docking studies; 3gvu has a good
˚
resolution of 2.05 A. The enzyme has an attached cocrys-
tallized inhibitor and therefore has a well-defined binding site.
A molecular docking study was performed using Auto Dock
Vina software (Trott & Olson, 2010). The protein–ligand
interactions revealed
a binding free energy ÁG =
ꢄ7.4 kcal molꢄ1, showing a lower value than those of protein–
pyrimidine derivatives, which have additional heterocycles
and several functional groups in their structures. The docking
results showed that the amino group of the pyrimidine moiety
was simultaneously anchored by hydrogen-bonding inter-
actions with Asp427 and His407 (Fig. 7).
Figure 7
3D diagram of the interactions of compound PPA in the active site of
tyrosine kinase (TK) showing two hydrogen bonds with Asp427 and
Hyst407. The atoms are coloured by atom type (carbon is black, nitrogen
is blue and oxygen is red) and hydrogen bonds are represented by green
dotted lines.
A parallel molecular simulation work was also performed,
where the PPA ligand interacted with the protein 2hyy, a
protein that had originally been used in molecular simulation
calculations with the compound imatinib, showing results
similar to those found with the protein 3gvu.
dependent density functional theory (TD-DFT) (Casida et al.,
1998) with the 6-311G++(d,p) basis set-optimized structure to
evaluate the energetic capacity of the molecule. The probable
excited states, theoretical electronic excitation energies,
oscillator strengths and absorption wavelengths were eval-
uated. Table 5 shows the oscillator strength, the energy values
of the HOMO and LUMO, as well as the HOMO–LUMO
energy gap. The measured values of the absorption wave-
lengths (ꢇmax) of PPA are shown in Fig. 6(a), and these values
4. Conclusions
The existence of dimers in the crystal is evidenced by the
formation of R22(8) N—Hꢁ ꢁ ꢁN hydrogen-bonded rings, as well
as by the shift of the N—H stretching vibration to lower
wavenumbers in the solid state relative to those in the gas
phase.
The calculation of the interaction energies between pairs of
molecules visualized the electrostatic terms as the dominant
factor against the dispersion factor in the crystal-growth
process.
The molecule analyzed in this work is structurally distinct
with respect to the position of the N atom in the pyridine ring
compared with the structure of imatinib, an excellent inhibitor
of Bcr-Abl tyrosine kinase. The interaction energies of this
relatively small ligand in the active pocket of the protein
indicate its potential and have inspired us to undertake a
synthetic study to identify better pharmacophores against
chronic myelogenous leukemia.
¨
can be assigned to the ꢀ–ꢀ* transition (Gokce et al., 2016).
From Fig. 6(b), it can be seen that the HOMO is uniformly
distributed on the pyrimidine ring and the amino group, and
that this orbital is partially distributed on the pyridine ring,
whereas the LUMO is uniformly distributed on the pyrimidine
and pyridine rings without any density on the amino group.
This behaviour is consistent with a donor–acceptor unit, where
the amino group acts as a donor and the pyridine and pyri-
midine rings act as acceptors. The absorption of specific
wavelengths in the UV–Vis region affects the appearance of
the low electron-density zones in the molecule, which in this
case correspond to the region close to the amino group.
Using the HOMO and LUMO orbital energies, the ioni-
zation energy and electron affinity can be expressed as I =
ꢄEHOMO and A = ꢄELUMO. The hardness, ꢌ, and chemical
potential, ꢄ, can be found from the following relationships ꢌ =
(I ꢄ A)/2 and ꢄ = ꢄ(I + A)/2, where I and A are the first
ionization potential and electron affinity of the chemical
species, respectively (Parr & Pearson, 1983). Thus, for the
Acknowledgements
RMF is grateful to Universidad del Valle for the support
received for the realization of the CI 71073 project. The
ꢃ
1688 Moreno-Fuquen et al.
Analysis of an imatinib-like template
Acta Cryst. (2019). C75, 1681–1689

research papers
Joule, J. A. & Mills, K. (2010). Editors. Heterocyclic Chemistry, 5th ed.
Oxford: Wiley.
Lee, C., Yang, W. & Parr, R. G. (1988). Phys. Rev. B, 37, 785–789.
Lu, T. & Chen, F. (2012). J. Comput. Chem. 33, 580–592.
Mackenzie, C. F., Spackman, P. R., Jayatilaka, D. & Spackman, M. A.
(2017). IUCrJ, 4, 575–587.
authors also express their gratitude to Professor C. W.
¨
Lehmann of the Max-Planck-Institut fur Kohlenforschung,
Germany, for collection of the diffraction data.
Funding information
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe,
P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. &
Wood, P. A. (2008). J. Appl. Cryst. 41, 466–470.
Mary, Y. S., Panicker, C. Y. & Varghese, H. T. (2010). Int. J. Chem. Sci.
8, 1071–1076.
McKinnon, J. J., Spackman, M. A. & Mitchell, A. S. (2004). Acta
Cryst. B60, 627–668.
Nakamura, N., Okawa, H., Inazu, T. & Kida, S. (1982). Bull. Chem.
Soc. Jpn, 55, 2400–2403.
Nielsen, A. B. & Holder, A. J. (2009). GaussView 5.0. Gaussian Inc.,
Pittsburgh, USA. https://gaussian.com/gaussview6/.
Padwa, A., Woolhouse, A. D., Katritzky, A. R. & Rees, C. W. (1984).
In Comprehensive Heterocyclic Chemistry. Oxford University
Press.
Funding for this research was provided by: Universidad del
Valle (grant No. 71073).
References
Agarwal, N., Raghuwanshi, S. K., Upadhyay, D. N., Shukla, P. K. &
Ram, V. J. (2000). Bioorg. Med. Chem. Lett. 10, 703–706.
Amir, M., Javed, S. A. & Kumar, H. (2007). Indian J. Pharm. Sci. 69,
337–343.
Athokpam, B., Ramesh, S. & McKenzie, R. (2017). Chem. Phys. 488–
489, 43–54.
Bailey, S. W. & Ayling, J. E. (2009). Proc. Natl Acad. Sci. 106, 15424–
15429.
Parr, R. G. & Pearson, R. G. (1983). J. Am. Chem. Soc. 105, 7512–
7516.
Porter, A. E. A. (1979). In Diazines and Benzodiazines, Vol. 14,
Oxford: Pregamon Press; Amsterdam: Elsevier Science BV.
Rana, K., Kaur, B. & Kumar, B. (2004). Indian J. Chem. Sect. B, 43,
1553–1557.
Becke, A. D. (1993). J. Chem. Phys. 98, 1372–1377.
Bejan, E., Haddou, H. A., Daran, J.-C. & Balavoine, G. G. A. (1996).
Synthesis, 1996, 1012–1018.
Bettendorff, L., Mastrogiacomo, F., Kish, S. J. & Grisar, T. (1996). J.
Neurochem. 66, 250–258.
Bettendorff, L., Wirtzfeld, B., Makarchikov, A. F., Mazzucchelli, G.,
´ ´
Roeges, N. P. G. (1994). In A Guide to Complete Interpretation of
Infrared Spectra of Organic Structures. New York: Wiley.
Sakaki, S., Kato, K., Miyazaki, T., Musashi, Y., Ohkubo, K., Ihara, H.
& Hirayama, C. (1993). J. Chem. Soc. Faraday Trans. 89, 659–
664.
Sarcher, C., Farsadpour, S., Taghizadeh Ghoochany, L., Sun, Y., Thiel,
W. R. & Roesky, P. W. (2014). Dalton Trans. 43, 2397–2405.
Sharma, P., Rane, N. & Gurram, V. K. (2004). Bioorg. Med. Chem.
Lett. 14, 4185–4190.
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.
Socrates, G. (1981). In Infrared Characteristic Group Frequencies.
New York: John Wiley and Sons.
Sondhi, S. M., Jain, S., Dwivedi, A. D., Shukla, R. & Raghubir, R.
(2008). Indian J. Chem. Sect. B, 47, 136–143.
Frederich, M., Gigliobianco, T., Gangolf, M., De Pauw, E.,
Angenot, L. & Wins, P. (2007). Nat. Chem. Biol. 3, 211–212.
Brown, D. J. (2009). In The Chemistry of Heterocyclic Compounds,
The Pyrimidines. New York: John Wiley and Sons.
Bruker (2006). DATCOL. Bruker AXS Inc., Madison, Wisconsin,
USA.
Bruker (2012). SADABS. Bruker AXS Inc., Madison, Wisconsin,
USA.
¨
¨ ¨
Buyukmurat, Y., Akalin, E., Ozel, A. & Akyuz, S. (1999). J. Mol.
Struct. 482–483, 579–584.
Casida, M. E., Jamorski, C., Casida, K. C. & Salahub, D. R. (1998). J.
Chem. Phys. 108, 4439–4449.
Chahwan, R., Wontakal, S. N. & Roa, S. (2010). Trends Genet. 26,
443–448.
Duisenberg, A. J. M., Kroon-Batenburg, L. M. J. & Schreurs, A. M. M.
(2003). J. Appl. Cryst. 36, 220–229.
Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.
Fleming, I. (1976). In Frontier Orbitals and Organic Chemical
Reactions. New York: John Wiley and Sons.
¨
Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm, 11, 19–32.
Trott, O. & Olson, A. J. (2010). J. Comput. Chem. 31, 455–461.
Turro, N. J. (2005). PNAS, 102, 10766–10770.
Xie, F., Zhao, H., Zhao, L., Lou, L. & Hu, Y. (2009). Bioorg. Med.
Chem. Lett. 19, 275–278.
Gavezzotti, A. (2005). Z. Kristallogr. 220, 499–510.
¨
Gokce, H., Ozturk, N., Ceylan, U., Alpaslan, Y. B. & Alpaslan, G.
¨
¨
(2016). Spectrochim. Acta A Mol. Biomol. Spectrosc. 163, 170–180.
¨
Zajac, M. A., Zakrzewski, A. G., Kowal, M. G. & Narayan, S. (2003).
Synth. Commun. 33, 3291–3297.
´
Zempleni, J., Galloway, J. R. & McCormick, D. B. (1996). Am. J. Clin.
Nutr. 63, 54–66.
Jamroz, M. H. (2013). Spectrochim. Acta A Mol. Biomol. Spectrosc.
114, 220–230.
ꢃ
Acta Cryst. (2019). C75, 1681–1689
Moreno-Fuquen et al.
Analysis of an imatinib-like template 1689

supporting information
supporting information
Acta Cryst. (2019). C75, 1681-1689 [https://doi.org/10.1107/S2053229619015523]
Synthesis, spectroscopic (FT–IR and UV–Vis), crystallographic and theoretical
studies, and amolecular docking simulation of an imatinib-like template
Rodolfo Moreno-Fuquen, Kevin Arango-Daraviña, Esteban Garcia, Juan-C. Tenorio and Javier
Ellena
Computing details
Data collection: DATCOL (Bruker, 2006); cell refinement: EVALCCD (Duisenberg et al., 2003); data reduction:
EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used
to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: ORTEP-3 (Farrugia, 2012), Mercury (Macrae
et al., 2008) and CrystalExplorer (McKinnon et al., 2004); software used to prepare material for publication:
SHELXL2014 (Sheldrick, 2015b).
4-(Pyridin-2-yl)pyrimidin-2-amine
Crystal data
C9H8N4
Dx = 1.388 Mg m−3
Mr = 172.19
Melting point: 413 K
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 4441 reflections
θ = 3.1–30.0°
Monoclinic, I2/a
a = 11.4608 (15) Å
b = 5.3791 (9) Å
c = 26.740 (4) Å
β = 91.457 (12)°
V = 1647.9 (4) Å3
Z = 8
µ = 0.09 mm−1
T = 293 K
Block, colourless
0.40 × 0.23 × 0.20 mm
F(000) = 720
Data collection
Bruker Enraf–Nonius KappaCCD
diffractometer
4441 measured reflections
2379 independent reflections
1688 reflections with I > 2σ(I)
Rint = 0.020
θmax = 30.0°, θmin = 3.1°
h = −16→11
k = −7→7
Radiation source: 0.2 x 2mm2 focus rotating
anode
Detector resolution: 18.02 pixels mm-1
CCD φ– and ω–scans
Absorption correction: gaussian
(SADABS; Bruker, 2012)
l = −31→37
T
min = 0.624, Tmax = 0.995
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.046
wR(F2) = 0.134
2379 reflections
126 parameters
0 restraints
Hydrogen site location: mixed
S = 1.03
Acta Cryst. (2019). C75, 1681-1689
sup-1

supporting information
H atoms treated by a mixture of independent
and constrained refinement
w = 1/[σ2(Fo2) + (0.0583P)2 + 0.5919P]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max < 0.001
Δρmax = 0.22 e Å−3
Δρmin = −0.22 e Å−3
Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance
matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles;
correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate
(isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Refinement. The crystal structure was solved with SHELXT (Sheldrick, 2014) and refined with SHELXL (Sheldrick,
2014). Anisotropic atomic displacement parameters were introduced for all non-hydrogen atoms.
Structure pictures were drawn with ORTEP (Farrugia, 2012), Mercury (Macrae et al., 2008) and CrystalExplorer
(McKinnon et al., 2004).
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
x
y
z
Uiso*/Ueq
N1
N2
N3
N4
C1
C2
H2
C3
H3
C4
C5
C6
H6
C7
H7
C8
H8
C9
H9
H4A
H4B
0.59793 (10)
0.49244 (9)
0.67213 (11)
0.40143 (12)
0.50044 (11)
0.69358 (12)
0.763316
0.69520 (12)
0.763313
0.58989 (11)
0.58070 (11)
0.48303 (12)
0.420375
0.47957 (13)
0.415261
0.57305 (14)
0.573555
0.66543 (14)
0.727581
0.3371 (19)
0.4016 (15)
0.8075 (2)
0.4940 (2)
0.1998 (3)
0.7523 (3)
0.6820 (3)
0.7359 (3)
0.816777
0.5499 (3)
0.505318
0.4316 (2)
0.2278 (2)
0.0784 (3)
0.105298
−0.1109 (3)
−0.215904
−0.1415 (3)
−0.268033
0.0180 (3)
−0.002133
0.677 (4)
0.54174 (4)
0.58498 (4)
0.67891 (5)
0.52808 (5)
0.55227 (5)
0.56694 (5)
0.560470
0.60189 (5)
0.619289
0.60997 (5)
0.64725 (5)
0.64859 (5)
0.626471
0.68304 (5)
0.684306
0.71553 (6)
0.739234
0.71233 (6)
0.735011
0.5350 (7)
0.5056 (7)
0.0397 (3)
0.0334 (3)
0.0475 (3)
0.0458 (3)
0.0336 (3)
0.0444 (4)
0.053*
0.0411 (3)
0.049*
0.0320 (3)
0.0325 (3)
0.0369 (3)
0.044*
0.0420 (3)
0.050*
0.0476 (4)
0.057*
0.0540 (4)
0.065*
0.066 (6)*
0.057 (5)*
0.880 (4)
Atomic displacement parameters (Å2)
U11
U22
U33
U12
U13
U23
N1
N2
N3
N4
C1
C2
0.0365 (6)
0.0286 (5)
0.0353 (6)
0.0347 (7)
0.0319 (6)
0.0322 (7)
0.0410 (7)
0.0365 (6)
0.0509 (8)
0.0508 (8)
0.0356 (7)
0.0519 (9)
0.0416 (6)
−0.0022 (5)
0.0018 (5)
−0.0016 (6)
0.0001 (6)
0.0022 (5)
−0.0066 (7)
0.0005 (5)
−0.0007 (4)
−0.0114 (5)
−0.0058 (5)
0.0003 (5)
0.0000 (6)
0.0065 (5)
0.0024 (4)
0.0148 (6)
0.0169 (6)
−0.0010 (5)
0.0087 (7)
0.0349 (5)
0.0555 (7)
0.0516 (7)
0.0332 (6)
0.0492 (8)
Acta Cryst. (2019). C75, 1681-1689
sup-2

supporting information
C3
C4
C5
C6
C7
C8
C9
0.0281 (6)
0.0285 (6)
0.0289 (6)
0.0329 (6)
0.0411 (7)
0.0503 (9)
0.0449 (8)
0.0491 (9)
0.0347 (7)
0.0344 (7)
0.0405 (8)
0.0396 (8)
0.0425 (8)
0.0565 (10)
0.0457 (7)
0.0329 (6)
0.0343 (6)
0.0372 (6)
0.0457 (7)
0.0500 (8)
0.0599 (9)
−0.0006 (6)
0.0025 (5)
0.0035 (5)
−0.0005 (6)
−0.0040 (6)
0.0030 (7)
0.0017 (8)
−0.0036 (5)
0.0010 (4)
−0.0004 (4)
−0.0021 (5)
0.0058 (6)
0.0020 (6)
−0.0150 (7)
0.0081 (6)
−0.0003 (5)
0.0005 (5)
−0.0017 (6)
0.0007 (6)
0.0132 (7)
0.0196 (8)
Geometric parameters (Å, º)
N1—C2
N1—C1
N2—C4
N2—C1
N3—C9
N3—C5
N4—C1
N4—H4A
N4—H4B
C2—C3
C2—H2
1.3291 (17)
C3—C4
1.3862 (19)
0.9300
1.3413 (18)
1.3297 (16)
1.3420 (17)
1.3286 (19)
1.3386 (16)
1.3459 (17)
0.87 (2)
0.91 (2)
1.369 (2)
0.9300
C3—H3
C4—C5
C5—C6
C6—C7
C6—H6
C7—C8
C7—H7
C8—C9
C8—H8
C9—H9
1.4875 (18)
1.3792 (19)
1.374 (2)
0.9300
1.372 (2)
0.9300
1.367 (2)
0.9300
0.9300
C2—N1—C1
C4—N2—C1
C9—N3—C5
C1—N4—H4A
C1—N4—H4B
H4A—N4—H4B
N1—C1—N2
N1—C1—N4
N2—C1—N4
N1—C2—C3
N1—C2—H2
C3—C2—H2
C2—C3—C4
C2—C3—H3
C4—C3—H3
N2—C4—C3
N2—C4—C5
115.38 (12)
116.56 (11)
116.77 (13)
118.6 (13)
120.8 (11)
120.6 (18)
125.95 (12)
117.02 (13)
117.03 (12)
123.68 (13)
118.2
118.2
116.43 (12)
121.8
121.8
121.97 (12)
116.73 (11)
C3—C4—C5
N3—C5—C6
N3—C5—C4
C6—C5—C4
C7—C6—C5
C7—C6—H6
C5—C6—H6
C8—C7—C6
C8—C7—H7
C6—C7—H7
C9—C8—C7
C9—C8—H8
C7—C8—H8
N3—C9—C8
N3—C9—H9
C8—C9—H9
121.30 (11)
122.74 (12)
116.04 (12)
121.22 (11)
119.10 (12)
120.4
120.4
118.56 (14)
120.7
120.7
118.59 (14)
120.7
120.7
124.21 (14)
117.9
117.9
C2—N1—C1—N2
C2—N1—C1—N4
C4—N2—C1—N1
C4—N2—C1—N4
C1—N1—C2—C3
N1—C2—C3—C4
C1—N2—C4—C3
C1—N2—C4—C5
−0.6 (2)
178.87 (13)
1.8 (2)
−177.71 (12)
−0.8 (2)
0.9 (2)
C9—N3—C5—C4
N2—C4—C5—N3
C3—C4—C5—N3
N2—C4—C5—C6
C3—C4—C5—C6
N3—C5—C6—C7
C4—C5—C6—C7
C5—C6—C7—C8
−179.77 (13)
−167.20 (12)
12.78 (19)
12.77 (19)
−167.24 (13)
−1.4 (2)
−1.58 (19)
178.40 (11)
178.66 (12)
1.1 (2)
Acta Cryst. (2019). C75, 1681-1689
sup-3

supporting information
C2—C3—C4—N2
C2—C3—C4—C5
C9—N3—C5—C6
0.4 (2)
−179.61 (13)
0.2 (2)
C6—C7—C8—C9
C5—N3—C9—C8
C7—C8—C9—N3
0.2 (2)
1.2 (3)
−1.4 (3)
Hydrogen-bond geometry (Å, º)
D—H···A
N4—H4B···N1i
D—H
0.91 (2)
H···A
D···A
D—H···A
2.10 (2)
3.0154 (19)
175.8 (16)
Symmetry code: (i) −x+1, −y+2, −z+1.
Acta Cryst. (2019). C75, 1681-1689
sup-4