Intermolecular interactions in antipyrine-like derivatives 2-halo-: N -(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazol-4-yl)benzamides: X-ray structure, Hirshfeld surface analysis and DFT calculations

Article abstract of DOI:10.1039/d0nj03958f

The synthesis, X-ray structure characterization, Hirshfeld surface analysis and DFT calculations of two new antipyrine derivatives are reported herein. Particularly, 2-bromo-N-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)benzamide (1) and 2-chloro-N-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)benzamide (2) are synthesized in good yields and characterized spectroscopically. Both compounds are isostructural and crystallize in the monoclinic P21/c space group. The crystal packing of both compounds is mainly stabilized by a combination of N-H?O and C-H?O hydrogen bonds. In addition, C-H?π and lone pair?π contacts were observed. Their solid-state structures have been analyzed through Hirshfeld surface analysis, including the evaluation of the different energy frameworks, indicating that the molecular sheets are primarily formed by hydrogen bonds and the stabilization is dominated via the electrostatic energy contribution. These studies are complemented with DFT calculations (B3LYP-D3/def2-TZVP), and a combination of QTAIM/NCIplot analyses disclosing that the H-bonding interactions are energetically relevant (ranging from 0.9 to 6.1 kcal mol-1), however the total binding energies of the different assemblies are dominated by a combination of π-interactions (of the type C-H?π, π?π, and lone pair halogen?π) that are able to stabilize cooperatively the assemblies up to 12 kcal mol-1.

Full text of DOI:10.1039/d0nj03958f

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Page 1 of 35
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Intermolecular interactions in antipyrine-like derivatives 2-halo-N-(1,5-dimeDthOIy: 1l0-.310-3o9x/Do0-NJ03958F
2-phenyl-2,3-dihydro-1-H-pyrazol-4-yl)benzamides: X-ray structure, Hirshfeld surface
analysis and DFT calculations
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a
a
b
c
c

Aamer Saeed, Asma Khurshid, Ulrich Flörke, Gustavo A. Echeverría, Oscar E. Piro, Diego
M. Gil,d,* Mariana Rocha,e Antonio Frontera,f Hesham R. El-Seedi,g,h Amara Mumtaz,i
Mauricio F. Erbenj*
a Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad, Pakistan.
b Department Chemie, Fakultät für Naturwissenschaften, Universität Paderborn, Warburgerstrasse 100,
D-33098 Paderborn, Germany
c Departamento de Física, Facultad de Ciencias Exactas, Universidad Nacional de La Plata e Instituto de
Física La Plata, IFLP (UNLP, CONICET, CCT-La Plata), C. C. 67, 1900 La Plata, Argentina.
d
INBIOFAL (CONICET-UNT). Instituto de Química Orgánica. Facultad de Bioquímica, Química y
Farmacia. Universidad Nacional de Tucumán. Ayacucho 471. T4000INI. San Miguel de Tucumán.
Argentina.
e
INBIOFAL (CONICET-UNT). Cátedra de Física. Facultad de Agronomía y Zootecnia. Universidad
Nacional de Tucumán. Av. Néstor Kirchner 1900. 4000. San Miguel de Tucumán. Argentina.
f Departament de Química, Universitat de les Illes Balears, Crta de Valldemossa km 7.5, 07122 Palma
de Mallorca (Baleares), Spain.
g College of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
h Al-Rayan Colleges, Medina 42541, Saudi Arabia.
i Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060,
Pakistan.
j CEQUINOR (UNLP-CONICET, CCT-La Plata), Departamento de Química, Facultad de Ciencias
Exactas, Universidad Nacional de La Plata, Boulevard 120 e/ 60 y 64 Nº1465 La Plata B1900, Buenos
Aires, Argentina.
 Corresponding authors: aamersaeed@yahoo.com (A.S.), diego.gil@fbqf.unt.edu.ar
(D.M.G.), erben@quimica.unlp.edu.ar (M.F.E.).
1

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Abstract
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The synthesis, structural X-ray characterization, Hirshfeld surface analysis and DFT
calculations of two new antipyrine derivatives are reported herein. Particularly, 2-bromo-N-
(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)benzamide (1) and 2-chloro-N-
(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)benzamide (2) are synthesized in
good yields and characterized spectroscopically. Both compounds are isostructural and
crystallize in the monoclinic P21/c space group. The crystal packing of both compounds is
mainly stabilized by a combination of N-H···O and C-H···O hydrogen bonds. In addition, C-
H···π and lone pair···π contacts were observed. Their solid-state structures have been analyzed
through Hirshfeld surface analysis, including the evaluation of the different energy frameworks,
indicating that the molecular sheets are primarily formed by hydrogen bonds and the
stabilization is dominated via the electrostatic energy contribution. These studies are
complemented with DFT calculations (B3LYP-D3/def2-TZVP), and a combination of
QTAIM/NCIplot analyses disclosing that the H-bonding interactions are energetically relevant
(ranging from 0.9 to 6.1 kcal/mol), however the total binding energies of the different
assemblies are dominated by a combination of π-interactions (of the type C-H···π, π···π, and
lone pair halogen···π) that are able to stabilize cooperatively the assemblies up to 12 kcal/mol.
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Keywords: Antipyrine derivatives; X-ray structure; Non-covalent interactions; Hirshfeld
surfaces; Energy frameworks
2

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1. Introduction
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Interest in antipyrine derivatives (APDs) can be traced back to the synthesis of the first
of such derivatives, namely aminophenazone, by Knorr in 1833 and have been the subject
matter of research in a variety of fields [1]. Aminophenazone derivatives have been shown to
possess pharmacological applications as antipyretic [2], analgesic [3], and anti-inflammatory
agents [4, 5]. The presence of amide linkage confers to aminophenazone moiety useful
biological activities. Since amides are an important class of organic compounds, they are
synthesized in a number of ways, including either direct coupling of carboxylic acids and
amines at high temperatures or through microwave-assisted methodologies and by means of
organo-catalysts. The exploration of amidic linkage in various drugs has disclosed the
importance of amides and broadened the scope of their pharmacological applications as
anthelmintic [6], antihistamine [7], antifungal [8], and antibacterial [9, 10]. Hybrid compounds
containing the antipyrine and thiazolyl or thiadiazolyl groups have been tailored to act as
potential non-acidic anti-inflammatory agents [11].
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Crystal engineering and supramolecular interactions, including non-covalent
interactions, have attracted considerable attention in the design of new receptors and
supramolecular materials [12-15]. Non-covalent interactions such as hydrogen bonding,
halogen bonding, C-H···π interactions, π-π stacking, dispersive interactions, σ-hole
interactions, π-hole interactions, and other weak contacts play crucial roles in various fields of
medicinal chemistry and materials science [16-20]. It is well-known that the crystal packing is
the result of the synergistic contributions of different types of strong and weak non-covalent
interactions and it is very important to study the cooperativity and competition of these non-
covalent interactions. A proper understanding of these interactions is crucial to extrapolate
structure-activity/property relationships.
We report here the synthesis and X-ray crystal structure of two new antipyrine
derivatives, namely 2-bromo-N-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-
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yl)benzamide (1) and 2-chloro-N-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-
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yl)benzamide (2). Hirshfeld surface analysis was used to determine quantitatively the
intermolecular interactions controlling the crystal packing of both compounds. In addition, we
have calculated the interaction energies, including energy frameworks. The concept of energy
frameworks allows for a better understanding of the intermolecular interactions as it graphically
represents the total interaction energies or its individual components as cylindrical tubes joining
molecules. The radii of these cylinders are mainly related with the strength of the corresponding
intermolecular contacts. These calculations are of crucial importance in the evaluation of the
contributions to the total intermolecular energies in molecular pairs from different structural
motifs.
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2. Experimental
2.1. Synthesis. A calculated amount of substituted aromatic acids 1 (0.1 g, 0.5 mmol) was
refluxed for 1-2 hours with thionyl chloride (0.03 mL, 0.5 mmol) to form the respective acid
halides. This was accompanied by the evolution of volatile gases like sulphur dioxide and
hydrogen chloride, respectively. A solution of 4-aminophenazone (0.1 g, 0.5 mmol) dissolved
in pyridine (0.03 mL, 0.5 mmol) was added to the acid halide formed in situ and the reaction
mixture was refluxed for 3 hours (Scheme I). On formation of the product, confirmed by thin
layer chromatography (TLC), the reaction mixture was filtered and the solid product purified
by recrystallization in aqueous ethanol. A tentative mechanism for the formation of the
benzamide moieties through the reaction of 4-aminophenazone and acyl halides is depicted in
the Scheme S1 (ESI).
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O
O
Reflux
+
SOCl2
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Cl
OH
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O
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NH2
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pyridine
reflux 3 h
+
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O
-HCl
N
Cl
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X
X= Br (1) and Cl (2)
Scheme I. Synthesis of compounds 1 and 2.
2.1.1- 2-Bromo-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pryazole-4-yl)benzamide (1):
Brown crystals, yield: 87%, m.p: 108-109 °C ; IR (KBr): 3151 (CONH), 2990, 2832, (Csp3-H),
1678 (CONH), 1423, 1332 (Csp3-H bending): 1H-NMR (CDCl3, 300MHz): δ 7.81 (s, 1H, N-
H), 7.66-7.28 (m, 9H, Ar-H), 3.15 (s, 3H, CH3-N-pyrazolone), 2.48 (s, 3H, CH3-Csp2-
pyrazolone); 13C-NMR (CDCl3, 75MHz): δ 166.31 (CONH), 161.19 (-C=C-CO-N-
2
2
pyrazolone), 149.37 (C6H4Br-CO-Csp -ipso), 137.29 (C6H5-Csp -ipso), 134.37 (-C=C-
2
2
pyrazolone), 133.46 (-C=C-pyrazolone), 131.56 (C6H4Br-Csp -para), 129.63 (C6H4Br-Csp -meta),
2
2
2
129.33 (C6H5-Csp -meta), 127.56 (C6H5-Csp -para), 124.40 (C6H5-Csp -ortho), 36.09 (CH3-N-
pyrazolone), 12.81 (CH3-CSP2- pyrazolone). GC-MS (m/z): 387 (M+), 341, 321 (100%), 202,
119, 91. LC-MS (m/z) %: M+386 (1:1), 368, 214, 203. Elemental analysis calculated for
C18H16BrN3O2: C 59.42, H 4.09, N 9.21 %; found: C 59.47, H 4.06, N 9.19 %.
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2.1.2-
2-Chloro-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pryazole-4-yDl)ObI:e1n0.z10a3m9/Did0NeJ03958F
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(2): Yellow crystalline solid; yield: 82%, m.p: 103-104 °C; IR (KBr): 3150 (CONH), 2991,
2865, (Csp3-H), 1675 (CONH), 1435, 1346 (Csp3-H bending): 1H-NMR (CDCl3, 300MHz): δ
7.64-7.60 (m, 3H, Ar-H), 7.45 (m, 2H, Ar-H), 7.40 (m, 3H, Ar-H), 7.37-7.26 (m, 2H, Ar-H, s,
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1H, N-H), 3.13 (s, 3H, CH3-N-pyrazolone), 2.41 (s, 3H, CH3-Csp2-pyrazolone); C-NMR
2
(CDCl3, 75MHz): δ 166.25 (-CONH), 161.36 (-C=C-CO-N- pyrazolone), 149.45 (C6H5-Csp -
2
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ipso), 137.40 (C6H4Cl-CO-Csp -para), 134.55 (C6H4Cl-CO-Csp -ipso), 133.40 (-C=C-
2
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pyrazolone), 131.45 (-C=C-pyrazolone), 129.63 (C6H4Cl-Csp -ortho), 129.24 (C6H5-Csp -meta),
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2
2
127.48 (C6H4Cl-Csp -ortho), 126.98 (C6H4Cl-Csp -meta), 124.21 (C6H4Cl-Csp -meta), 119.70
(C6H5-Csp -para ), 108.31 (C6H5-Csp -ortho), 36.17 (CH3-N-), 12.79 (CH3-CSP2-). LC-MS (m/z)
%: 342 (M+ with clear 3:1 35/37Cl isotopic ratio), 214. Elemental analysis calculated for
C18H16ClN3O2: C 61.21, H 6.78, N 14.40 %; found C 61.25, H 6.72, N 14.42 %.
2
2
2.2. Instrumentation. Melting points were determined with a Gallenkamp melting point
apparatus (MP-D) and the values are uncorrected. Infrared absorption spectra of samples
sandwiched between KBr pellets were recorded with a Shimadzu IR 460 spectrophotometer.
1H-NMR spectra were obtained with a Bruker 300 NMR MHz spectrometer in CDCl3 solution,
using TMS as an internal reference. 13CNMR spectra were obtained by (75 MHz) NMR
spectrometer in CDCl3 as solvent. Thin layer chromatography was performed on pre-coated
silica gel aluminum plates (layer thickness 0.2 mm, HF 254, Reidal-de-Haen from Merck).
Chromatogram was recorded using ultraviolet light (254 and 260 nm). Mass spectra were
recorded on a LC/MSD InfinityLab LC Series 1260 from Agilent Technologies. Elemental
analysis was performed on a LECO CHNS 932 instrument.
2.3. Crystal data and structure refinement. For 1, X-ray diffraction intensities were collected
on a Bruker SMART APEX CCD with graphite-monochromated MoKα (=0.71073 Å)
radiation. Data were corrected semi-empirically for absorption from equivalent reflections. For
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2, the measurements were performed on an Oxford Xcalibur Gemini, Eos CCD diDffOrIa: 1c0t.o10m39e/Dt0eNrJ03958F
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with graphite-monochromated CuKα (=1.54178 Å) radiation. X-ray reflection intensities were
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collected ( scans with  and κ-offsets), integrated and scaled with CrysAlisPro [21] suite of
programs. The unit cell parameters were obtained by least-squares refinement (based on the
angular settings for all collected reflections with intensities larger than seven times the standard
deviation of measurement errors) using CrysAlisPro. Data were corrected empirically for
absorption employing the multi-scan method implemented in CrysAlisPro. Both structures were
solved by direct methods with SHELXS of the SHELX suite of programs [22] and the molecular
model refined with anisotropic displacement parameters for all non-H atoms by full-matrix
least-squares procedure with SHELXL of the same package. For 1, H-atom were located in
difference Fourier maps and refined at idealized positions riding on the carbon or nitrogen
atoms to which they are attached with isotropic displacement parameters Uiso(H) = 1.2Ueq(C/N)
or 1.5Ueq(CH3) and C-H 0.95-0.98 Å and N-H 0.88 Å. For 2, all hydrogen atoms were located
among the first sixteen most intense peaks in a Fourier difference Fourier map phased on the
heavier atoms and refined at their found positions with isotropic displacement parameters. Both
CH3 groups converged to staggered conformations.
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Crystal data and structure refinement results are summarized in Table 1. Crystallographic
structural data have been deposited at the Cambridge Crystallographic Data Centre (CCDC).
Enquiries for data can be direct to: Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, UK, CB2 1EZ or (e-mail) deposit@ccdc.cam.ac.uk or (fax) +44 (0) 1223 336033.
Any request to the Cambridge Crystallographic Data Centre for this material should quote the
full literature citation and the reference number CCDC 1884126 (1) and 2008322 (2).
Table 1. Crystal data and structure refinement results for compounds (1) and (2).
__________________________________________________________________________________________
Empirical formula
C18 H16 Br N3 O2
C18 H16 Cl N3 O2
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Formula weight
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
386.25
130(2) K
0.71073 Å
Monoclinic
P 21/c
a = 14.1326(15) Å
b = 6.1144(6) Å
c = 20.190(2) Å
β = 106.033(2)°
341.79
297(2) K
1.54184 Å
Monoclinic
P 21/c
a = 13.985(1) Å
b = 6.2373(4) Å
c = 20.226(1) Å
β = 105.334(7)°
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3
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Volume
1676.6(3) Å
1701.5(2) Å
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Z, density (calculated)
4, 1.530 Mg/m
4, 1.334 Mg/m
-1
-1
Absorption coefficient
F(000)
2.467 mm
784
2.115 mm
712
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Crystal size
ϑ-range for data collection
Index ranges
0.44 x 0.21 x 0.18 mm 0.184 x 0.157 x 0.040 mm
1.50 to 27.88°
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-7 ≤ k ≤ 8
-26 ≤ l ≤ 24
15171
3987 [R(int) = 0.027]
3323
100% to ϑ = 27.88°
4.534 to 72.347°
-14 ≤ h ≤ 17
-7 ≤ k ≤ 3
-24 ≤ l ≤ 24
6646
Reflections collected
Independent reflections
Observed reflections [I>2σ(I)]
Completeness
3303 [R(int) = 0.027]
2251
99.9 % to ϑ = 67.684°
2
Refinement method
Data / restraints / parameters
Full-matrix least-squares on F
3987 / 0 / 223
3303 / 0 / 281
2
Goodness-of-fit on F
Final R indices [I>2σ(I)]
1.062
1.010
R1 = 0.0334
wR2 = 0.0837
R1 = 0.0432
wR2 = 0.0882
R1 = 0.0489
wR2 = 0.1272
R1 = 0.0774
wR2 = 0.1518
R indices (all data)
-3
-3
Largest diff. peak and hole
0.638 and -0.257 e Å
0.202 and -0.263 e Å
R1=ΣFo-Fc/ΣFo, wR2=[Σw(Fo2-Fc2)2/Σw(Fo 2)2]1/2. For 1 the largest diff. peak is 0.77 Å from
Br1 position.
2.4. Hirshfeld surface calculations. Hirshfeld surfaces [23] and their associated two-
dimensional fingerprint plots [24] can be considered as very convenient tools for the exploration
of intermolecular interactions in numerous organic and inorganic compounds [25]. Different
functions describe specific properties of the Hirshfeld surface (dnorm, shape index, or
curvedness) allowing for intuitive recognition and visual analysis of interactions between
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different molecules. In the case of dnorm surface, red spots are associated with contacts between
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atoms, which are shorter than the sum of van der Waals (vdW) radii, and for this reason are
frequently used to visualize close contacts such as hydrogen bonds. The 2D fingerprint plots
are used as a graphical summary of the contact distances to the Hirshfeld surface and allow us
to decode and quantify the intermolecular contacts in the crystal lattice. Hirshfeld surfaces and
2D fingerprint plots were explored with the CrystalExplorer17.5 program [26] on crystal
structures imported from CIF files.
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2.5. Theoretical methods. The calculations of non-covalent interactions and molecular
electrostatic potential (MEP) surfaces were carried out using Gaussian-16 [27] at the B3LYP-
D3/def2-TZVP level of theory. The Grimme’s D3 dispersion correction has been used in the
calculations [28]. To evaluate the interactions in the solid state, the crystallographic coordinates
were used and only the position of the H-bonds has been optimized. This procedure and level
of theory has been successfully used to evaluate similar interactions in related systems [29].
The interaction energies were computed by calculating the difference between the energies of
the isolated monomers and the ones of their assembly. The QTAIM analysis [30] and NCIplot
index [31] have been computed at the same level of theory by means of the AIMAll program
[32].
3. Results and discussion
3.1. Description of crystal structures of compounds 1-2.
Figures 1a and 2a show an ORTEP [33] view of the solid-state molecular structures of
1 and 2, respectively. Table 2 compares a selection of observed bond lengths and angles with
the corresponding computed values at B3LYP/6-311++G(d,p) approximation. The optimized
molecular structures of 1 and 2 are shown in Figure S1, ESI. The optimized molecular
geometries of both molecules agree well with that observed from the X-ray structural studies.
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As shown in Table 2, the small differences between observed and computed DgOeI:o10m.10e3t9r/iDc0aNlJ03958F
parameters in compounds 1-2 can be attributed to the fact that theoretical calculations have been
performed assuming isolated molecules (in gas-phase) whereas the experimental values
correspond to the solid state where the intermolecular interactions play an important role.
Molecules 1 and 2 are structurally closed related and isostructural to each other. Both
compounds crystallize in the monoclinic space group P21/c, with one molecule in the
asymmetric unit. The amide unit [-C(O)-NH-] is twisted with respect to both 2,3-dihydro-1-H-
pyrazol-4yl and 2-halophenyl ring, with dihedral angles of 61.34 and 55.99º, respectively in 1,
66.70 and 59.63º in 2. The dihedral angles between the 2,3-dihydro-1H-pyrazol-4yl and 2-
halophenyl rings are 12.19 and 11.64º for compounds 1 and 2, respectively, while 2,3-dihydro-
1-H-pyrazol-4yl and phenyl rings subtend dihedral angles of 43.77º for 1 and 46.55º for 2. The
rotation of the amide group with respect to both the 2-bromophenyl and 2-chlorophenyl rings
are due to steric repulsion between the halogen and the O-atom from the carbonyl group. In
addition, the conformation adopted between the amide group and the 2-halophenyl rings in both
compounds are stabilized by intramolecular O···X halogen bonds, with Br1···O1 and Cl1···O2
distances of 3.237(2) and 3.194(3) Å, respectively. The C-N imide bond lengths equal to
1.346(3) and 1.347(4) Å for 1 and 2, respectively, are considerably shorter than expected for
single C(sp2)-N(sp2) bonds, whose reported average length is 1.472(5) Å [34] and the carbonyl
bond lengths are in the range expected for imide carbonyl bonds. This feature can be attributed
to the importance of resonance structures in this type of compounds. The C=O bond lengths
corresponding to the 2,3-dihydro-1-H-pyrazol-4yl ring are 1.241(2) and 1.237(3) Å for
compounds 1 and 2, respectively. The N3-N2-C13 and N2-N1-C1 angles are 118.3(1) and
118.1(2)º for compounds 1 and 2. These values are significantly smaller than the ideal value of
120º expected for N-atoms with sp2 hybridization. These results could be probably attributed to
the repulsion between the nitrogen lone pairs and the adjacent N-N bond. In general, the
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geometrical parameters of both compounds are in good agreement with relatedDcOoI:m10.p10o3u9/nDd0NsJ03958F
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reported in literature [35-39].
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Table 2: Selected experimental (X-ray) and calculated [B3LYP/6-
311++G(d,p)] geometrical parameters for compounds 1 and 2.
Compound 1 Exp.
Calc. Compound 2
Exp.
Calc.
C3-Br1
C2-C1
C1-O1
C1-N1
C8-N1
C8-C11
C8-C9
C9-O2
C9-N2
1.898(2) 1.909 C14-Cl1
1.504(3) 1.509 C13-C12
1.227(2) 1.224 C12-O2
1.346(3) 1.369 C12-N3
1.412(2) 1.397 C8-N3
1.367(3) 1.363 C8-C9
1.431(3) 1.460 C7-C8
1.241(2) 1.230 C7-O1
1.394(2) 1.394 C7-N1
1.363(2) 1.412 C9-N2
1.407(2) 1.415 N2-N1
1.473(2) 1.473 C10-N2
1.420(2) 1.419 C1-N1
3.237(2) 3.179 Cl1···O2
115.6(2) 113.3 C13-C12-N3
122.0(2) 130.6 C12-N3-C8
122.0(2) 113.9 N3-C8-C7
129.3(2) 137.1 N3-C8-C9
118.3(1) 119.8 N2-N1-C1
1.734(3) 1.755
1.502(3) 1.509
1.215(3) 1.224
1.347(4) 1.370
1.417(3) 1.397
1.364(3) 1.363
1.427(4) 1.460
1.237(3) 1.230
1.392(3) 1.394
1.364(3) 1.412
1.401(3) 1.415
1.473(4) 1.473
1.422(3) 1.419
3.194(3) 3.141
115.5(2) 113.1
121.6(2) 130.5
122.0(2) 114.0
128.6(2) 137.0
118.1(2) 119.8
C11-N3
N3-N2
C10-N3
C13-N2
Br1···O1
C2-C1-N1
C1-N1-C8
N1-C8-C9
N1-C8-C11
N3-N2-C13
C3-C2-C1-N1 127.9(2) 132.4 C14-C13-C12-N3 -123.8(3) -131.6
C2-C1-N1-C8 163.3(2) 172.8 C13-C12-N3-C8 -163.4(2) -172.6
C1-N1-C8-C9 -106.1(2) -163.2 C12-N3-C8-C7
102.1(3) 162.4
The crystal packing of both compounds 1-2 is stabilized by intermolecular N-H···O
hydrogen bonds involving the O-atom of the pyrazol carbonyl group and the H-atom of the
amide group, leading to the formation of inversion dimers with 푅22(10) graph-set ring motif
(Figures 1b and 2b, Table 3). Both structures are further stabilized by C-H···O hydrogen bonds,
as shown in Figures 1 and 2. The H6A and H17 atoms interact with the O-atoms of the pyrazole
ring through C-H···O hydrogen bonds giving 푅22(18) graph-set motifs (Figures 1d, 2c). The
supramolecular assembly of both compounds is further stabilized by C-H···π interactions. For
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compound 1, the C16-H16A···Cg3 interactions (H16A···Cg3 distance = 2.97 Å, C16A-
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H16A···Cg3 angle = 141º) involve the centroid Cg3 (C13-C18) and the H16A of the phenyl
ring. On the other hand, for compound 2, C4-H4···Cg2 contacts (H4···Cg2 distance = 3.00 Å,
C4-H4···Cg2 angle = 143º) involve the benzene ring (C1-C6) and the H4 of the phenyl ring of
other molecule.
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Figure 1. a) Molecular structure of 1 with displacement ellipsoids drawn at the 30% probability
level, intramolecular non-bonding contacts shown as dashed lines, b) intermolecular N-H···O
interactions as dashed lines, c) combination of H-bonds and lone pair···π interactions, d)
formation of C-H···O hydrogen bonds and C-H···π interactions.
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Figure 2. a) Molecular structure of 2 with displacement ellipsoids drawn at the 30% probability
level. Intramolecular non-bonding contacts shown as dashed lines, b) intermolecular N-H···O
interactions as dashed lines, c) formation of C-H···O hydrogen bonds and C-H···π interactions,
d) formation of C-H···O H-bonds.
Interestingly, the Cg3 and Cg2 centroids for 1 and 2 are respectively linked to the
halogen atom through lone pair···π interaction. For 1, the distance between the bromide Br1
atom and the centroid Cg3 of the π face is 4.477 Å [α C3-Br1···Cg3 = 158.1º] (Figure 1c). The
shorter separation distance Br1···C15 = 3.5280(2) Å and the value of angle α indicate
significant lone pair ···π interactions [40]. Similar results were obtained for 2, with Cl1···Cg2
distance of 4.550 Å [α C14-Cl1···Cg2 = 159.7º, Cl1···C5 distance = 3.573 Å].
Table 3: Geometrical parameters (Å, º) of the hydrogen bonds in compounds 1-2.
D-H···A
Compound 1
N1-H1···O2i
D-H
H···A
D···A < (D-H···A)
0.88
0.95
0.98
1.93
2.54
2.39
2.805(2)
3.418(3)
2.981(3)
171
154
118
C6-H6A···O2ii
C10-H10A···O1iii
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C10-H10C···O2iv
C12-H12A···O1iv
Compound 2
0.98
0.98
2.46
2.47
3.403(2)
3.207(3)
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N3-H3N···O1v
0.890(3) 1.945(3) 2.833(3)
175
118
128
158
155
C10-H10C···O2vi 0.901(3) 2.510(3) 3.037(3)
C11-H11C···O2vii 0.952(3) 2.559(3) 3.233(3)
C10-H10A···O1vii 1.000(3) 2.531(3) 3.479(3)
C17-H17···O1viii 0.904(3) 2.656(3) 3.497(3)
Symmetry codes: (i) -x,-y,-z; (ii) -x, 2-y, -z+1; (iii) -x, y-1/2, -z+3/2;
(iv) x, y-1, z; (v) –x+1, -y, -z; (vi) –x+1, +y+1/2, -z+1/2; (vii) x,
+y+1, +z; (viii) –x+1, -y-1, -z.
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3.2. Hirshfeld surface analysis
The Hirshfeld surfaces of compounds 1-2 showed in Figure 3 were mapped over dnorm
,
shape index and curvedness properties and illustrate the nature and extent of different
intermolecular interactions. The short and dominant intermolecular contacts are shown as bright
red areas in the Hirshfeld surface mapped over dnorm function indicating the existence of
hydrogen bonds. The two near and larger red spots labeled 1 in the dnorm map of both compounds
are due to the formation of dimers via N1-H1···O2 (1) and N3-H3···O1 (2) bonds. These
hydrogen bonds involve the acceptor O atom from the carbonyl group of the pyrazole ring. A
similar pattern of bright red areas attributed to N-H···O hydrogen bonds was observed in a new
o-hydroxyphenyl diazepine derivative in which the crystal packing is mainly influenced by this
type of hydrogen bonds [41]. These contacts (Figure 1b and 2b) represent the stronger hydrogen
bonding interactions in the crystal packing, as was reflected in the geometrical parameters listed
in Table 3. The red regions labeled 2 in the dnorm maps are attributed to C10-H10A···O1 (1) and
C11-H11C···O2 (2) hydrogen bonds. The deep red areas labeled 3 and 4 in the Hirshfed surface
of 1 are attributed to C10-H10C···O2 and C12-H12A···O1 bonds involving the O-atoms from
the pyrazole ring and amide groups, respectively. The dnorm map of 1 shows two red spots
labeled 3 and 5 respectively attributed to C10-H10A···O1 and C10-H10C···O2 bonds. In
addition, visible red spots labeled 6 (1) and 4 (2) in the dnorm surfaces are respectively attributed
to C6-H6A···O2 and C17-H17···O1 bonds, involving the O-atom of the pyrazole ring as
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acceptor and the H atom of the 2-halophenyl ring to form graph-set motifs 푅2(18), as shown
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in Figures 1 and 2. The Hirshfeld surface of 1 shows small red spots (labeled 5) associated with
lone pair···π interactions involving the lone pair of the bromine atom and the Cg3 centroid, as
described previously. The red spot labeled 6 in the dnorm surface of 2 could be attributed to
O2···C10 tetrel bonding interactions, with d(O2···C1) = 3.037 Å [42].
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Furthermore, the Hirshfeld surfaces were mapped with shape index and curvedness
functions to evaluate the presence of π···π stacking interactions, which are not clearly visible
in the analysis of the crystal structure [43]. In the shape index diagram of both compounds
(Figure 3, column 2), the pattern of convex blue and concave red triangles, highlighted in red,
indicate the existence of π-stacking interactions in the structure of both compounds, involving
the 2-halophenyl ring. In accordance with the structural results, the π···π stacking interactions
involve the pyrazole ring (centroid Cg1) and the 2-bromophenyl (centroid 2) and 2-
chlorophenyl (centroid 3) rings, with Cg···Cg distances of 4.7189(5) for 1 and 4.6696(4) Å for
2. These interactions are also visible as relatively large and green flat regions delineated by the
red circle on the curvedness surfaces of both compounds (Figure 3, column 3).
dnorm
Shape index
Curvedness
Compound 1
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Figure 3. Hirshfeld surfaces of compounds 1-2 mapped with dnorm (with the molecule in two
different orientations), shape index and curvedness. For description of labels and highlighting
circles, see the text.
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The full 2D fingerprint plots of the main intermolecular interactions of the compounds
are depicted in Figure 4. The van der Waals forces (H···H intermolecular contacts) are in the
middle of scattered points, with minimum values of (de + di = 2.4 Å) and have a major
contribution to the crystal packing of 1 (39.2%) and 2 (40.6%). The closest H···O/O···H
contacts (labeled 1) are represented on the fingerprint plots by characteristic sharp spikes at de
+ di = 1.8 Å contributing 16.8 and 17.4% of the total Hirshfeld surface area.
The H···C/C···H contacts (labeled 2) comprise 26.7% (1) and 25.8% (2) of the total
Hirshfed surface area. As shown in the fingerprint plots of both compounds, the pair of “wings”
highlighted in red, indicate the existence of C-H···π intermolecular contacts, as described
previously [44]. The broad spikes labeled 3 and 4 in the fingerprint plots are attributed to
H···Br/Br···H (12.5%) for 1 and H···Cl/Cl···H (12.3%) for 2. In addition, the fingerprint plots
of both compounds show C···X/X···C contacts associated to lone pair ··· π interactions
described previously.
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Figure 4. Full 2D fingerprint plots of compounds 1-2 showing (1) H···O/O···H, (2)
H···C/C···H, (3) H···Br/Br···H, (4) H···Cl/Cl···H contacts.
3.3. Enrichment ratio
The enrichment ratios (Exy) of contacts between the different chemical species X and
Y were calculated from the chemical composition on the Hirshfeld surface to highlight which
contacts are statically favored and kept in the crystal packing of the compounds [45]. The EXY
is defined as a ratio between the proportion of actual contacts CXY in the crystal and the
theoretical proportion of random contacts RXY. The CXX and CXY values are used to calculate
the proportion SX of different chemical species on the molecular surface. The random contacts
RXY were computed from the corresponding SX and SY proportions by using of probability
products. Enrichment ratios larger than unity indicate that these contacts are over-represented
in the crystal packing with respect to the chemical composition on the Hirshfeld surface. The
chemical species that tend to avoid contacts are represented by enrichment values lower than
unity [45].
The EXY values for the compounds are presented in Table 4, and the complete
information is provided in Table S1, ESI. The largest contributions to the Hirshfeld surfaces
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are from H···C/C···H, H···O/O···H and H···X/X···H (X= Br, Cl) and their enrichment ratio
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values are in the 1.3-1.4 range, with the same values for both compounds. The computed EXY
values are significantly higher than unity, showing high propensity to form C-H···π, C-H···O
or N-H···O and C-H···X hydrogen bonds, as result of high and most proportion SH of hydrogen
atoms at the molecular surface. The propensity of the 2-halophenyl and pyrazole rings to form
π···π stacking interactions is much more extensive in 2, as reflected by the highly increased
ECN/NC values of 1.75 and 2.3, respectively, which are associated to C···N/N···C contacts [43b,
46]. These results indicate that the π···π stacking interactions are more favored in 2, in
accordance with the geometrical parameters of the π···π stacking interactions of both
compounds [43b, 46]. For 2, the value of Cg1···Cg3 inter-centroid distance of 4.6696(4) Å is
lower as compared with Cg1···Cg2 inter-centroid distance of 4.7189(5) Å observed in 1. These
results indicate that the π···π stacking interactions in 1 are weaker. On the other hand, the
likelihood to form N···O/O···N contacts are high in the crystal packing, with ENO values of
1.40 (1) and 1.50 (2). The ENH and ECC values show that N···H and C···C contacts are slightly
favored, whereas the C···O/O···C contacts are practically avoided.
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Table 4: Enrichment ratios (EXY) of the main intermolecular interactions for compounds 1-2.
Interaction
EXY
Compound 1 Compound 2
H···H
0.85
1.3
0.9
1.4
1.3
0.09
0.04
1.75
0.9
0.85
1.3
0.9
1.4
1.3
0.1
0.04
2.3
0.7
1.5
H···C/C···H
H···N/N···H
H···O/O···H
H···X/X···H
C···C
C···O/O···C
C···N/N···C
C···X/X···C
N···O/O···N
1.4
3.4. Energy frameworks
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The energy frameworks of compounds 1-2 were calculated with CrystalExplorer17.5
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program [26] using the HF/3-21G approximation. Quantification of the framework energies is
an important method for understanding the topology of the overall interactions of molecules in
the crystal packing. This technique provides information about the types of energy responsible
for the supramolecular assembly in the solid. The interaction energies between pair of
molecules are described as the sum of electrostatic (Eele), polarization (Epol), dispersion (Edis)
and exchange-repulsion (Erep) terms [47]. A cluster of molecules within a radius of 3.8 Å for a
central molecule was generated [47]. The scale factors used are 1.019, 0.651, 0.901 and 0.811
for electrostatic, dispersion, polarization and repulsion interactions, respectively [48]. Figure 5
shows the energy frameworks constructed with the calculated interaction energies for 1 and the
frameworks of 2 are shown in Figure S2, ESI. The interaction energies for selected molecular
pair of compounds 1-2 are presented in Table 5.
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From Table 5, it can be appreciated that the highest total energies of -87.8 kJ/mol (1)
and -86.7 kJ/mol (2) correspond to the molecular pair formed by N-H···O bonds generating
푅22(10) ring motifs (see Figures 1b and 2b) being the shorter contact and the strongest
interaction of all the hydrogen bonds that are responsible of the crystal packing of 1 and 2.
These results are in agreement with the geometrical parameters shown in Table 3 and with the
energetic values obtained for the same interactions in a related compound [49]. On the other
hand, the N-H···O bonds shows a relatively high electrostatic energy of -81.6 kJ/mol (1) and -
76.8 kJ/mol (2). The second important contribution (of about 18 %) to the total energy is for
pair of molecules with Etot values of -42.3 kJ/mol (1) and -41.8 kJ/mol (2), associated with C-
H···O bonds. For 2, the pair of molecules interacting with Etot value of -36.7 kJ/mol involves
C17-H17···O1 bonds, with an important contribution of electrostatic energy (-19.3 kJ/mol), in
agreement with reported values [49]. For 1, the total energy of -37.9 kJ/mol involves C-H···O
and C-H···Br bonds, as shown in Table 5. In 1, the molecular pair with total energy value of -
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36.7 kJ/mol involves C6-H6A···O2 bonds and the presence of C-H···π interaction, which
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further increases the stability of the dimer. These features may also explain the dominance of
the dispersion energy in the molecular pair as a result of the attractive dispersive nature of π-
interactions [50].
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From the analysis of the energy frameworks we have extracted net energies. For both
compounds, the sum of dispersion energies (-237.2 kJ/mol for 1 and -211.7 kJ/mol for 2) are
greater than that of electrostatic energies (-138.5 and -128.4 kJ/mol), hence indicating that
remarkably dispersion energy dominates over the electrostatic energy, as shown in the thickness
of the cylinders along the c-axis. Figure 5 clearly indicates that the electrostatic energy
frameworks are relevant from the dimers stacked along the a-axis and b-axis as can be seen by
thick cylinders linking molecules [47, 48].
Compound 1
a-axis
b-axis
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c-axis
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Figure 5. Energy frameworks along a-axis (above), b-axis (middle), c-axis (botton) for
compound 1, showing separate electrostatic (left, red), and dispersion (middle, green)
components, and total energy interactions (right, blue). The tube size (scale factor) used in all
energy frameworks was 90 and the cut-off was 5.00 kJ/mol.
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Table 5: Interaction energies (Etot) partitioned into electrostatic (Eele), polarization (Epol), dispersion
(Edis) and exchange-repulsion (Erep) contributions (kJ/mol) for selected molecular pairs.
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Interactions
d(H···A/Cg)[d],
< D-H···A
A N[b] Symmetry code R[c]
Eele Epol Edis Erep ETot
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Compound 1
C12-H12A···O1
C10-H10C···O2
2.473(3), 131
2.464(3), 160
2
x, y, z
6.11
5.88
-17.1 -6.6 -45.9 25.5
-5.9 -14.0 -49.0 26.4
-42.3
C10-H10A···O1
C10-H10A···Br1
C15-H15A···Br1
2.393(3), 118
3.906(3), 95.48
3.084(3), 110,31
2
-x, y+1/2, -z+1/2
-37.9
C4-H4A···Br1
N1-H1···O2
H4-H5
3.099(3), 136.98
2.076(2), 175
2.40
1
1
1
2
2
-x, -y, -z
12.35
5.41
-4.8
-0.5 -12.6 10.5
-8.0
-87.8
-8.6
-3.8
-4.7
-x, -y, -z
-81.6 -27.1 -72.6 96.6
-x, -y, -z
13.85
15.27
14.13
-2.2
0.4
-0.8
-0.3
-0.2
-8.4
-5.3
-4.4
2.2
1.0
1.4
H5A-H15A
Br1···Cg(3)
2.70
x, -y+1/2, z+1/2
x, y, z
4.477(5)
-1.7
C6-H6A···O2
C18-H18···Cg(2)
2.540(3), 154
2.920, 141
1
2
-x, -y, -z
8.28
-19.8 -9.4 -22.6 12.4
-36.7
-11.8
C16-H16···Cg(3)
2.970(2), 139
-x, y+1/2, -z+1/2
15.23
-5.8
-1.4 -16.4 12.1
Compound 2
H4···Cg(3)
3.00
2
2
1
1
1
2
x, -y+1/2, z+1/2
15.26
14.78
13.38
13.99
8.05
0.2
-1.6
-4.4
-1.3
-0.2
-0.7
-0.5
-0.3
-4.9
-7.2
-8.9
-3.2
0.8
1.7
6.2
0.6
-3.7
-7.1
H17···Cg(3)
C15-H15···Cl
C3-H3·· Cl
2.70
-x, -y, -z
-x, -y, -z
x, y, z
2.687(0), 81.44
3.528(2), 78.8
2.656(3), 155
1.945(3),175
-7.9
-3.9
C17-H17···O1
N3-H3N···O1
-x, -y, -z
-x, -y, -z
-19.3 -8.7 -20.5 8.8
-76.8 -25.6 -69.6 87.4
-36.7
-86.7
5.04
C10-H10A···O1
C11-H11C···O2
2.531(3), 158
2.559(3), 128
2
x, y, z
6.24
-16.0 -6.4 -41.1 19.4
-4.2 -12.9 -40.9 17.6
-41.8
C10-H10C···O2
C6-H6···O2
2.510(2), 118
2.902(2), 161.8
1
2
-x, y+1/2, -z+1/2
-x, y+1/2, -z+1/2
5.96
-35.2
-11.8
H4 ···Cg(2)*
3.00
14.08
-5.0
-1.3 -15.4 9.9
[a] Molecule color; [b] Number of molecules at R distance; [c] distance (Å) between molecular centroids (mean
atomic position); [d] Geometry of H-bonds (Å, °) and H ···Cg distance (Å); Cg(2), Cg(2)*and Cg(3) are the
centroids of the N2/N3/C11/C8/C9, N1/N2/C9/C8/C7 and C13-C18 rings, respectively.
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3.5. Theoretical study
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In order to complement the energetic analysis discussed above, we have also evaluated
the important motifs of compounds 1 and 2 shown in Figures 1 and 2. For this purpose, we have
performed B3LYP-D3/def2-TZVP calculations in four dimers of each compound in
combination with QTAIM analysis and NCIplot calculations. Using the QTAIM analysis we
have also evaluated each individual H-bond in the 푅22(10) and 푅22(18) graph-set motifs.
First of all, we have computed the molecular electrostatic potential (MEP) surface [51]
of compound 1 (also as model of 2) to locate the most positive and negative parts of the
molecule, which is represented in Figure 6. It can be observed that the most positive region
corresponds to the H-atoms of the amido group (+33 kcal/mol) as expected. Moreover, the H-
atoms of the N–CH3 group also exhibits a large and positive MEP value (+25 kcal/mol) thus
explaining its participation in multiple C–H···O interactions in the solid state of 1 and 2. The
aromatic H-atoms are also positive (up to 16 kcal/mol, see Figure 6a). The most negative value
is located at the O-atom of the pyrazolone ring (–45 kcal/mol) that is slightly more nucleophilic
than the amidic O-atom (–42 kcal/mol). Finally, the MEP is negative over the phenyl rings,
which present a significant anisotropy. That is, the MEP values above and below the center of
the aromatic rings are quite different (up to 14 kcal/mol difference in the phenyl ring).
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Figure 6. (a,b) Two opposite views of the MEP surface of compound 1 (iso-surface = 0.001
a.u.) at the B3LYP-D3/def2-TZVP level of theory. The energies at selected points of the
surfaces are given in kcal/mol).
Figure 7 shows the QTAIM analysis [52] of three dimers of compounds 1 and 2, along
with the binding energies and the superposition of the NCIplot surfaces [53]. Those represented
in Figure 6a and b correspond to the 푅22(10) and 푅22(18) graph-set motifs of 1 and the
equivalent motifs of compound 2 are represented in Figure 6d and e. The QTAIM analysis
confirms the existence of the H-bonds in both motifs, each one characterized by a bond critical
point (CP) (red sphere) and bond path interconnecting the H and O-atoms. The NCIplot index
characterizes these H-bonds as small iso-surfaces which are blue (strong interaction) in the
푅22(10) motif and green (weak interaction) in the 푅22(18) graph-set motif. This is in line with
the MEP surface analysis, since the MEP value at the aromatic H-bonds is modest (up to 16
kcal/mol) compared to that at the N–H group. Agreeably, the binding energy of the 푅22(10)
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motif is large (–21.4 kcal/mol in 1 and –23.2 kcal/mol in 2) due to the strong H-bonds and
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additional contribution from aromatic interactions (see green iso-surfaces between the aromatic
and the 3-methylpyrazolone moiety). In contrast, the 푅22(18) graph-set motif presents more
modest interaction energies (–8.2 and –7.6 kcal/mol in 1 and 2, respectively). Figures 7c,f also
show additional motifs where a combination of C–H···O, C–H···π and X···π (X = Br and Cl)
interactions stabilizes the dimers. These type of interactions have been previously described in
the literature as recurrent forces in the solid state of a variety of compounds [54]. All these
interactions are confirmed by the existence of the corresponding bond CPs, bond paths and
NCIplot iso-surfaces. These motifs involve the methyl groups as H-bond donors, which are
more positive than the aromatic H-atoms, as revealed by the MEP surface analysis. This fact
likely explains the larger interaction energies obtained for these motifs (–12.2 kcal/mol for 1
and –11.9 kcal/mol for 2). In general, the interaction energies obtained for the three motifs
shown in Figure 7 are similar for Br and Cl, thus revealing that the halogen atom has a little
effect on the interaction energies.
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Figure 7. Combination of QTAIM (bond CP in red, ring Cp in yellow and cage CPDiOnI:b10l.u10e3)9/aDn0dNJ03958F
NCIplots of the three motifs of compound 1 (a-c) and 2 (d-f). The binding energies are also
indicated.
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Table 6 gathers the values or ρ(r), electronic potential energy density [V(r)] and
electronic kinetic energy density [G(r)] values at the bond critical points that characterize the
H-bonds, which are labeled in Figure 7. The dissociation energies of each H-bond based on the
V(r) QTAIM parameter [E = 0.5V(r)] [55] have been also included in Table 6. It can be
observed that for the 푅22(10) motif the sum of the contributions of both H-bonds is –8.8
kcal/mol in 1 and –12.2 kcal/mol for 2, thus confirming that these H-bonds are the strongest
ones in agreement with the NCIplot and MEP surface analysis. The stronger energies computed
for 2 are in good agreement with the experimental geometric features of the H-bonds (see Table
3), which indicate shorter H···O and longer N–H distances in compound 2 as compared to 1. It
is worthy to highlight that in these 푅22(10) motifs, the sum of the other forces (π–interactions
and other long-range interactions) is also very important. This contribution can be roughly
estimated by subtracting the QTAIM energies corresponding to the H-bonding to the total
interaction energies of the dimers [–21.4 –(–8.8) = –12.6 kcal/mol in 1 and –23.2 –(–12.2) = –
11.0 kcal/mol in 2]. For the 푅22(18) motif the H-bonding contribution is only –2.4 kcal/mol in
1 and –1.8 kcal/mol in 2, thus evidencing that these H-bonds are very weak, also in agreement
with the NCIplot. Finally, the H-bonds involving the methyl groups (CPs c and d) are stronger
than those involving the aromatic rings, in agreement with the MEP analysis. The –V(r) values
are smaller than the G(r) values at the bond CPs, thus confirming the noncovalent nature of the
H-bonds.
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Table 6. QTAIM ρ(r), V(r) and G(r) parameters at the bond CPs labelled in FigureD7OiI:n10a.1.0u3.9/aDn0dNJ03958F
predicted dissociation energies for each interaction using the electronic potential energy
densities.
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Compound
1
CP
ρ(r)
V(r)
G(r)
Edis (QTAIM)
a
b
c
d
a
b
c
d
0.0180
0.0068
0.0096
0.0090
0.0240
0.0053
0.0082
0.0078
–0.0139
–0.0038
–0.0057
–0.0049
–0.0193
–0.0029
–0.0048
–0.0041
0.0180
0.0053
0.0076
0.0066
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0.0041
0.0064
0.0056
4.4
1.2
1.8
1.5
6.1
0.9
1.5
1.3
2
Finally, two additional dimers dominated only by C–H···π interactions observed in the
solid state of both complexes have been analyzed (see Figure 8) energetically and using the
QTAIM/NCIplot computational tools. In both compounds the C–H···π interaction is
characterized by two bond CPs and bond paths connecting the aromatic H-atoms to two C-
atoms of the phenyl ring. The NCIplot shows a green iso-surface located between the aromatic
ring and both H-atoms, further confirming the existence and attractive nature of the interaction.
The dimerization energies are similar for both compounds (–3.0 kcal/mol in 1 and –3.1 kcal/mol
in 2) and in the range of energy interactions found for related organic compounds [48].
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Figure 8. Combination of QTAIM (bond CP in red and ring CP in yellow) and NCIplots of the
C–H···π motifs of compound 1 (a) and 2 (b). The binding energies are also indicated.
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4. Conclusions
Two novel phenazone derivatives have been synthesized and characterized, showing the
capability of obtaining phenazone-hybrid compounds through the reaction of 4-
aminophenazone and acyl halides. Their crystal structures were solved by X-ray diffraction
methods. The compounds are isostructural to each other and crystallize in the monoclinic P 21/c
space group, with Z= 4. The halo substitution of the phenyl ring in the position 2 leads to the
adoption of a conformation in which the amide group and the 2-halophenyl rings interact via
intramolecular O···X halogen bonds, with Br1···O1 and Cl1···O2 distances of 3.237(2) and
3.194(3) Å, respectively. Moreover, the crystal packing is also affected by the presence of the
2-halophenyl group through significant lone pair···π interaction.
The crystal structures of compounds 1-2 reveal that the intermolecular N-H···O, C-
H···O, C-H···π and lone pair···π interactions are the main driving interactions in the
supramolecular assembly formation. These interactions were studied through the Hirshfeld
surface analysis to reveal the nature and their contributions to the total Hirshfeld surface area.
In accordance with energy framework energy analysis, the N-H···O hydrogen bonds in both
compounds play an important role in the crystal packing, where the electrostatic term is
dominant. The dispersion energy values prevail over the electrostatic contribution in the
calculation of the solid-state interaction energies, hence indicating that the role of C-H···π and
lone pair ···π dispersion interactions are significant, as shown in the energy framework
diagrams along the c-axis. The interactions have been analyzed by combined QTAIM and
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NCIplot computational tools, which confirm the existence of such compounds and also the
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relevance of other interactions apart from the conventional N-H···O hydrogen bonds.
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Acknowledgments
Financial support from the MICIU of Spain (project CTQ2017-85821-R FEDER funds), Consejo
Nacional de Investigaciones Científicas y Técnicas, CONICET (Grant PIP 0651) and Facultad
de Ciencias Exactas, Universidad Nacional de La Plata, UNLP (Grants 11/X709 and 11/X794)
of Argentina is gratefully acknowledged. We thank the CTI (UIB) for computational facilities.
D.M.G., M.F.E., G.A.E. and O.E.P. are Research Fellows of CONICET. M.R. thanks CONICET
for a post-doctoral fellowship.
Electronic Supplementary Information. The general mechanism for synthesis of benzamide
derivatives of 4-aminophenazone is given in Scheme S1. The optimized molecular structures of
compounds 1 and 2 are shown in Figure S1. Figure S2 shows the energy frameworks along crystal
axis for compound 2. Table S1 lists the Hirshfeld contact surfaces, proportion of chemical type on
the molecular surface and random contacts of the main intermolecular interactions for compounds
1 and 2.
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