5-Iodo-1-Arylpyrazoles as Potential Benchmarks for Investigating the Tuning of the Halogen Bonding

: 5-Iodo-1-arylpyrazoles are interesting templates for investigating the halogen bond propensity in small molecules other than the already well-known halogenated molecules such as tetraﬂuorodiiodobenzene. Herein, we present six compounds with di ﬀ erent substitution on the aryl ring attached at position 1 of the pyrazoles and investigate them in the solid state in order to elucidate the halogen bonding signiﬁcance to the crystallographic landscape of such molecules. The substituents on the aryl ring are generally combinations of halogen atoms (Br, Cl) and various alkyl groups. Observed halogen bonding types spanned by these six 5-iodopyrazoles included a wide variety, namely, C–I · · · O, C–I · · · π , C–I · · · Br, C–I · · · N and C–Br · · · O interactions. By single crystal X-ray di ﬀ raction analysis combined with the descriptive Hirshfeld analysis, we discuss the role and inﬂuence of the halogen bonds among the intermolecular interactions.

The central concept of the halogen interactions is the so-called sigma-hole [33][34][35][36][37][38][39][40][41], which is briefly a formal positive potential on the extremity of the halogen atom that is more likely to interact with nucleophilic entities. Halogen bonding was first investigated in the case of halogen-halogen interactions which were defined as type I and type II [1,2,42], and more recently an unconventional type III halogen or di-σ-hole [43] has been reported ( Figure 1b). However, the concept was extended to different halogen-B interactions, where B could be any Lewis base or other electronegative molecular entity. More particularly, halogen-oxygen, halogen-nitrogen or halogen-π ( Figure 1c) interactions were reported both in liquid and solid state. We recently discovered that halogenated sydnones [44,45] and pyrazoles [46] are molecules with high potential for investigating the propensity of halogen bonding and its contribution among the other intermolecular interactions. We reported three types of halogen bonding in our investigations, all involving the iodine atom: I⋯N, I⋯O and I⋯π [46]. During our investigation, we also showed, with examples from the Cambridge Structural Database (CSD), that halogen interactions are important intermolecular forces which can either stabilize or even direct the crystalline network.
We proposed to expand our investigational endeavor to a library of iodinated pyrazoles by introducing also other halogen atoms such as bromine or different substituents on the phenyl ring of the 1-arylpyrazoles in order to study the halogen bonding and its relation to other intermolecular interactions.
Therefore, suitable crystals for six new 5-iodinated-1-arylpyrazoles were obtained by slow evaporation from different solvents and investigated by single crystal X-ray diffraction analysis and using descriptive tools such as Hirshfeld analysis and quantum computations.
Suitable crystals were grown by slow evaporation from acetonitrile (compounds 1, 2, 4 and 5) or a mixture of ethanol and dichloromethane 1:2 v/v (compounds 3 and 6)

X-ray Diffraction Analysis
X-ray diffraction measurements were carried out with a Rigaku Oxford-Diffraction XCALIBUR E CCD diffractometer equipped with graphite-monochromated MoKα radiation. The unit cell determination and data integration were carried out using the CrysAlis package of Oxford Diffraction [51]. The structures were solved by Intrinsic Phasing using Olex2 [52] software with the SHELXT [53] structure solution program and refined by full-matrix least-squares on F 2 with SHELXL-2015 [54] using an anisotropic model for non-hydrogen atoms. All H atoms attached to carbon were introduced in idealized positions (dCH = 0.96 Å) using the riding model. The molecular plots were obtained using the Olex2 program. Table 1 provides a summary of the crystallographic data together with refinement details for compounds. The geometric parameters are summarized in Table S1. The values of the geometrical parameters are in the expected ranges for compounds in this class. The (c) halogen-π interactions (over-the-atom, over-the-bond and over-the-ring).
We recently discovered that halogenated sydnones [44,45] and pyrazoles [46] are molecules with high potential for investigating the propensity of halogen bonding and its contribution among the other intermolecular interactions. We reported three types of halogen bonding in our investigations, all involving the iodine atom: I· · · N, I· · · O and I· · · π [46]. During our investigation, we also showed, with examples from the Cambridge Structural Database (CSD), that halogen interactions are important intermolecular forces which can either stabilize or even direct the crystalline network.
We proposed to expand our investigational endeavor to a library of iodinated pyrazoles by introducing also other halogen atoms such as bromine or different substituents on the phenyl ring of the 1-arylpyrazoles in order to study the halogen bonding and its relation to other intermolecular interactions.
Therefore, suitable crystals for six new 5-iodinated-1-arylpyrazoles were obtained by slow evaporation from different solvents and investigated by single crystal X-ray diffraction analysis and using descriptive tools such as Hirshfeld analysis and quantum computations.

X-ray Diffraction Analysis
X-ray diffraction measurements were carried out with a Rigaku Oxford-Diffraction XCALIBUR E CCD diffractometer equipped with graphite-monochromated MoKα radiation. The unit cell determination and data integration were carried out using the CrysAlis package of Oxford Diffraction [51]. The structures were solved by Intrinsic Phasing using Olex2 [52] software with the SHELXT [53] structure solution program and refined by full-matrix least-squares on F 2 with SHELXL-2015 [54] using an anisotropic model for non-hydrogen atoms. All H atoms attached to carbon were introduced in idealized positions (d CH = 0.96 Å) using the riding model. The molecular plots were obtained using the Olex2 program. Table 1

Hirshfeld Analysis
Hirshfeld analysis was performed using CystalExplorer [55,56]. By definition, the Hirshfeld surface maps intermolecular contacts, and essentially it is computed at the sum of de and di, the distances from the external atoms to the surface and internal atoms to the Hirshfeld surface, respectively [56]. Sums of distances shorter than the sum of the vdW radii of two neighboring atoms are marked with red spots, distances close to the vdW radii in white and distances larger than vdW in blue color. Moreover, the fingerprint plots [56] show a qualitative description of all the relevant contacts in the crystal packing, by plotting in a 2D graph di and de, which are the distances from the contact atoms to the Hirshfeld surface, creating a "heatmap" of non-covalent interactions.

Results and Discussion
In a recent study [46], we investigated the propensity for 5-iodopyrazoles ( Figure 2) to form halogen bonds. We observed the tendencies of 5-iodopyrazoles and 4-iodosydnones [44][45][46] to form halogen bond interactions with several Lewis bases by 13 C-NMR spectroscopy in solution and this subsequently prompted us to focus on solid-state interactions in such compounds. Interestingly, the iodine atom in the proposed 5-iodo-1-arylpyrazoles was found to be involved in C-I⋯N, C-I⋯O and C-I⋯π type interactions, and this was consistent with interactions observed in other similar structures from the CSD [46,57]. With the aim of extending our studies, we investigated a library of six new iodopyrazole structures by single crystal X-ray diffraction analysis. The structural variation of the six compounds was ensured by the different substituents on the aryl ring, which were chosen bearing in mind both steric factors that might be induced by bulky groups in the ortho position of the aryl residue, and the introduction of other halogen atoms such as Br or Cl, which had also proven to be involved in halogen non-covalent interactions.
Crystals of the pyrazoles 1-6 were subjected to single crystal X-ray diffraction analysis and the measured parameters are presented in Table 1. With the aim of extending our studies, we investigated a library of six new iodopyrazole structures by single crystal X-ray diffraction analysis. The structural variation of the six compounds was ensured by the different substituents on the aryl ring, which were chosen bearing in mind both steric factors that might be induced by bulky groups in the ortho position of the aryl residue, and the introduction of other halogen atoms such as Br or Cl, which had also proven to be involved in halogen non-covalent interactions.
Crystals of the pyrazoles 1-6 were subjected to single crystal X-ray diffraction analysis and the measured parameters are presented in Table 1.
where n is the number of reflections and p is the total number of parameters refined.

X-ray Crystallography
The solid-state structures of the compounds 1-6 were investigated by single crystal X-ray diffraction. According to this study, all the compounds crystallize with one molecule in the asymmetric unit, as depicted in Figure 3. There were no co-crystallized solvent molecules in any of the crystals. The bond distances and angles are summarized in Table S1. This series of 5-iodopyrazoles exhibited a similar molecular structure, their compositions differing only by the nature and position of the phenyl substituents. As a result of the predicted steric hindrance, the molecules were essentially non-planar. The dihedral angles between the 5-iodopyrazole and phenyl rings were in the range 76.4(1)-94.6(3) • .
where n is the number of reflections and p is the total number of parameters refined.

X-ray Crystallography
The solid-state structures of the compounds 1-6 were investigated by single crystal X-ray diffraction. According to this study, all the compounds crystallize with one molecule in the asymmetric unit, as depicted in Figure 3. There were no co-crystallized solvent molecules in any of the crystals. The bond distances and angles are summarized in Table S1. This series of 5iodopyrazoles exhibited a similar molecular structure, their compositions differing only by the nature and position of the phenyl substituents. As a result of the predicted steric hindrance, the molecules were essentially non-planar. The dihedral angles between the 5-iodopyrazole and phenyl rings were in the range 76.4(1)-94.6(3)°. The analysis of the crystal packing for the compounds investigated revealed a variety of supramolecular architectures, where the intermolecular interactions are driven by the presence of C-Br⋯O or C-I⋯O halogen bonding as well as, in the majority of the crystals, by C-H⋯O hydrogen bonding. The analysis of the crystal packing for the compounds investigated revealed a variety of supramolecular architectures, where the intermolecular interactions are driven by the presence of C-Br· · · O or C-I· · · O halogen bonding as well as, in the majority of the crystals, by C-H· · · O hydrogen bonding.
The X-ray diffraction study of compound 1 highlighted the iodine atom as being involved in C-I· · · O halogen bonding towards a carbonyl oxygen atom of an adjacent molecule, which leads to the formation of infinite supramolecular chains, as depicted in Figure 4. The X-ray diffraction study of compound 1 highlighted the iodine atom as being involved in C-I⋯O halogen bonding towards a carbonyl oxygen atom of an adjacent molecule, which leads to the formation of infinite supramolecular chains, as depicted in Figure 4. The crystal structure was built up via the parallel packing of discrete 2D layers, as shown in Figure 5. A similar packing of relatively isolated supramolecular layers ( Figure 6) was observed in the crystal of compound 2. Compared with compound 1, in 2, each layer was consolidated exclusively by C-H O intermolecular contacts with appropriate hydrogen bonding parameters. Short intermolecular contacts fulfilling the conditions of halogen bonding were not obvious in the crystal of 2 upon preliminary inspection, but an iodine-π interaction was highlighted by Hirshfeld surface analysis, which will be discussed later.  The crystal structure was built up via the parallel packing of discrete 2D layers, as shown in Figure 5. A similar packing of relatively isolated supramolecular layers ( Figure 6) was observed in the crystal of compound 2. Compared with compound 1, in 2, each layer was consolidated exclusively by C-H· · · O intermolecular contacts with appropriate hydrogen bonding parameters. Short intermolecular contacts fulfilling the conditions of halogen bonding were not obvious in the crystal of 2 upon preliminary inspection, but an iodine-π interaction was highlighted by Hirshfeld surface analysis, which will be discussed later. The X-ray diffraction study of compound 1 highlighted the iodine atom as being involved in C-I⋯O halogen bonding towards a carbonyl oxygen atom of an adjacent molecule, which leads to the formation of infinite supramolecular chains, as depicted in Figure 4.
The crystal structure was built up via the parallel packing of discrete 2D layers, as shown in Figure 5. A similar packing of relatively isolated supramolecular layers ( Figure 6) was observed in the crystal of compound 2. Compared with compound 1, in 2, each layer was consolidated exclusively by C-H O intermolecular contacts with appropriate hydrogen bonding parameters. Short intermolecular contacts fulfilling the conditions of halogen bonding were not obvious in the crystal of 2 upon preliminary inspection, but an iodine-π interaction was highlighted by Hirshfeld surface analysis, which will be discussed later.  As demonstrated by X-ray crystallography, the crystal packing of compound 3 was determined by C-Br⋯O and C-I⋯O halogen bonding, as well as by C-H⋯O hydrogen bonding. The intermolecular halogen bonds are depicted in Figure 7.
As could be observed, each molecule of compound 3 was involved in the formation of four halogen bonds with symmetry-related molecules: twice as a donor and twice as an acceptor of halogen. Due to the three-dimensional orientation of the halogen bonding, the molecular units were auto-assembled to form a dense 3D supramolecular network. A view of the 3D architecture is shown in Figure 8.
As demonstrated by X-ray crystallography, the crystal packing of compound 3 was determined by C-Br· · · O and C-I· · · O halogen bonding, as well as by C-H· · · O hydrogen bonding. The intermolecular halogen bonds are depicted in Figure 7. As demonstrated by X-ray crystallography, the crystal packing of compound 3 was determined by C-Br⋯O and C-I⋯O halogen bonding, as well as by C-H⋯O hydrogen bonding. The intermolecular halogen bonds are depicted in Figure 7.
As could be observed, each molecule of compound 3 was involved in the formation of four halogen bonds with symmetry-related molecules: twice as a donor and twice as an acceptor of halogen. Due to the three-dimensional orientation of the halogen bonding, the molecular units were auto-assembled to form a dense 3D supramolecular network. A view of the 3D architecture is shown in Figure 8.
As could be observed, each molecule of compound 3 was involved in the formation of four halogen bonds with symmetry-related molecules: twice as a donor and twice as an acceptor of halogen. Due to the three-dimensional orientation of the halogen bonding, the molecular units were auto-assembled to form a dense 3D supramolecular network. A view of the 3D architecture is shown in Figure 8.
Additionally, the 3D network was stabilized by an extended system of C-H⋯O short contacts, which can be interpreted as intermolecular hydrogen bonding. According to the X-ray diffraction study (Table 1), compounds 1 and 4 crystallize in the same space group (P21/c) with similar unit cell parameters. Consequently, due to some level of isostructurality, these compounds exhibited similar crystal packing features. Figure 9 illustrates the influence of C-I⋯O intermolecular interactions on the linear array arrangement in the crystal of 4, which closely resembled the supramolecular chain found in the crystal structure of 1. The shortest intermolecular I⋯Br contact which occurred in the crystal of compound 5 was found to be 3.6468(5) Å. As a result, the main crystal structure motif can be characterized as an infinite chain formed by C-I⋯Br halogen bonding, a view of which is depicted in Figure 10a. The analysis of the crystal packing showed that the chains were further interacting via C-H⋯O hydrogen bonds, which determined the presence of a tangled three-dimensional supramolecular network. A view of the crystal packing is shown in Figure 10b. As could be observed, the crystal structure was characterized as a parallel packing of 2D networks, which were interconnected through C-I⋯Br and C-H⋯O interlayer interactions.
Additionally, the 3D network was stabilized by an extended system of C-H· · · O short contacts, which can be interpreted as intermolecular hydrogen bonding. According to the X-ray diffraction study (Table 1), compounds 1 and 4 crystallize in the same space group (P2 1 /c) with similar unit cell parameters. Consequently, due to some level of isostructurality, these compounds exhibited similar crystal packing features. Figure 9 illustrates the influence of C-I· · · O intermolecular interactions on the linear array arrangement in the crystal of 4, which closely resembled the supramolecular chain found in the crystal structure of 1.
Additionally, the 3D network was stabilized by an extended system of C-H⋯O short contacts, which can be interpreted as intermolecular hydrogen bonding. According to the X-ray diffraction study (Table 1), compounds 1 and 4 crystallize in the same space group (P21/c) with similar unit cell parameters. Consequently, due to some level of isostructurality, these compounds exhibited similar crystal packing features. Figure 9 illustrates the influence of C-I⋯O intermolecular interactions on the linear array arrangement in the crystal of 4, which closely resembled the supramolecular chain found in the crystal structure of 1. The shortest intermolecular I⋯Br contact which occurred in the crystal of compound 5 was found to be 3.6468(5) Å. As a result, the main crystal structure motif can be characterized as an infinite chain formed by C-I⋯Br halogen bonding, a view of which is depicted in Figure 10a. The analysis of the crystal packing showed that the chains were further interacting via C-H⋯O hydrogen bonds, which determined the presence of a tangled three-dimensional supramolecular network. A view of the crystal packing is shown in Figure 10b. As could be observed, the crystal structure was characterized as a parallel packing of 2D networks, which were interconnected through C-I⋯Br and C-H⋯O interlayer interactions. The shortest intermolecular I· · · Br contact which occurred in the crystal of compound 5 was found to be 3.6468(5) Å. As a result, the main crystal structure motif can be characterized as an infinite chain formed by C-I· · · Br halogen bonding, a view of which is depicted in Figure 10a. The analysis of the crystal packing showed that the chains were further interacting via C-H· · · O hydrogen bonds, which determined the presence of a tangled three-dimensional supramolecular network. A view of the crystal packing is shown in Figure 10b. As could be observed, the crystal structure was characterized as a parallel packing of 2D networks, which were interconnected through C-I· · · Br and C-H· · · O interlayer interactions. In the crystal of 6, the molecules interacted through C-Br⋯O and a bifurcated C-I⋯O and C-I⋯N halogen bonding to form wave-like two-dimensional supramolecular layers, depicted in Figure 11. In turn, C-H⋯O hydrogen bonds interconnected these layers, thereby generating a three-dimensional architecture (see Figure 11b). In the crystal of 6, the molecules interacted through C-Br· · · O and a bifurcated C-I· · · O and C-I· · · N halogen bonding to form wave-like two-dimensional supramolecular layers, depicted in Figure 11. In turn, C-H· · · O hydrogen bonds interconnected these layers, thereby generating a three-dimensional architecture (see Figure 11b). Crystals 2020, 10, x FOR PEER REVIEW 10 of 22 a b Figure 11. (a) The formation of a 2D supramolecular layer in the crystal structure of 6. Halogen bond parameters:

Hirshfeld Analysis
Compound 1. The compound 1 has a methyl group attached to the ortho position of the phenyl ring. As is already known [46,57], substitution of this kind leads to a rotation of the phenyl ring out of the pyrazole plane in order to accommodate the steric hindrance. The most intuitively obvious halogen interaction based on previous observations is generally that between the iodine atom of one molecule and the oxygen atom in an ester group or the available nitrogen atom in the pyrazole ring of another molecule. In this case, molecule 1 presented an intermolecular C-I⋯O bond between the iodine atom and the O atom of the C=O group at position 3 of the pyrazole ring ( Figure 12) in a neighboring molecule.

Hirshfeld Analysis
Compound 1. The compound 1 has a methyl group attached to the ortho position of the phenyl ring. As is already known [46,57], substitution of this kind leads to a rotation of the phenyl ring out of the pyrazole plane in order to accommodate the steric hindrance. The most intuitively obvious halogen interaction based on previous observations is generally that between the iodine atom of one molecule and the oxygen atom in an ester group or the available nitrogen atom in the pyrazole ring of another molecule. In this case, molecule 1 presented an intermolecular C-I· · · O bond between the iodine atom and the O atom of the C=O group at position 3 of the pyrazole ring ( Figure 12 The Hirshfeld surface presents the strong C-I⋯O contact between the iodine and the carbonyl oxygen of the ester attached at C-3 of the pyrazole ring (A, B-red spots). Infinite chains along the C-I⋯O ran in antiparallel directions, and these were stacked together through C=O⋯H bonds(C) involving the oxygen in the ester group at C-4 of the pyrazole and H-6 of the phenyl group Compound 2. By adding a methyl group to the para position of the phenyl ring, one might expect that the newly introduced bulky group would show some influence on the packing of the molecules, and indeed in this case, C-I⋯π dimers ( Figure 13) between two inverted molecules were formed. These dimers are held together by hydrogen bonds involving the carbonyl groups of the esters and hydrogen atoms of the phenyl moiety. It has previously been shown that C-I⋯π dimers of this kind are not uncommon for phenylpyrazoles [46,57].  The Hirshfeld surface presents the strong C-I· · · O contact between the iodine and the carbonyl oxygen of the ester attached at C-3 of the pyrazole ring (A, B-red spots). Infinite chains along the C-I· · · O ran in antiparallel directions, and these were stacked together through C=O· · · H bonds(C) involving the oxygen in the ester group at C-4 of the pyrazole and H-6 of the phenyl group Compound 2. By adding a methyl group to the para position of the phenyl ring, one might expect that the newly introduced bulky group would show some influence on the packing of the molecules, and indeed in this case, C-I· · · π dimers ( Figure 13) between two inverted molecules were formed. These dimers are held together by hydrogen bonds involving the carbonyl groups of the esters and hydrogen atoms of the phenyl moiety. It has previously been shown that C-I· · · π dimers of this kind are not uncommon for phenylpyrazoles [46,57]. The Hirshfeld surface presents the strong C-I⋯O contact between the iodine and the carbonyl oxygen of the ester attached at C-3 of the pyrazole ring (A, B-red spots). Infinite chains along the C-I⋯O ran in antiparallel directions, and these were stacked together through C=O⋯H bonds(C) involving the oxygen in the ester group at C-4 of the pyrazole and H-6 of the phenyl group Compound 2. By adding a methyl group to the para position of the phenyl ring, one might expect that the newly introduced bulky group would show some influence on the packing of the molecules, and indeed in this case, C-I⋯π dimers ( Figure 13) between two inverted molecules were formed. These dimers are held together by hydrogen bonds involving the carbonyl groups of the esters and hydrogen atoms of the phenyl moiety. It has previously been shown that C-I⋯π dimers of this kind are not uncommon for phenylpyrazoles [46,57].  The Hirshfeld surface presents the short contacts specific to a C-I· · · π interaction and the strong hydrogen bond contacts (two red spots on the carbonyl oxygen marking a bifurcated O· · · H bond). Of course, one might say that such dimers can be formed in order to minimize the energy in the crystalline lattice, but the contribution of the C-I· · · π interaction is clear and the presence of the σ-hole of the iodine stabilizes such a dimeric structure. The nature of the C-I· · · π bond was assessed taking into account the directionality of the bond which clearly indicates a σ-hole interaction, in spite of a π-hole interaction with the lone-pair electrons of the iodine [35]. Additionally, the C-I· · · π contact could be characterized as an over-the-bond (or above-the-bond) type.
Compound 3. By replacing the methyl group in the para position of the phenyl ring with a Br atom, our expectation was that the Br atom with its σ-hole would show availability for halogen bonding. Both esters on the pyrazole ring engaged in hydrogen bonds forming dimers as depicted in the previous section.
These dimers were held together by strong C-I· · · O (A, B) bonds with the ester carbonyl at C-4 of the pyrazole. The interesting fact is that C-Br· · · O halogen bonds were also present with the -Oatom in the same ester moiety (A, C), and this is what we expected to observe by introducing a new halogen atom in the molecule. The Hirshfeld surface depicts very well the relevant contacts for these two halogen bonding patterns ( Figure 14). The Hirshfeld surface presents the short contacts specific to a C-I⋯π interaction and the strong hydrogen bond contacts (two red spots on the carbonyl oxygen marking a bifurcated O⋯H bond). Of course, one might say that such dimers can be formed in order to minimize the energy in the crystalline lattice, but the contribution of the C-I⋯π interaction is clear and the presence of the σ-hole of the iodine stabilizes such a dimeric structure. The nature of the C-I⋯π bond was assessed taking into account the directionality of the bond which clearly indicates a σ-hole interaction, in spite of a π-hole interaction with the lone-pair electrons of the iodine [35]. Additionally, the C-I⋯π contact could be characterized as an over-the-bond (or above-the-bond) type.
Compound 3. By replacing the methyl group in the para position of the phenyl ring with a Br atom, our expectation was that the Br atom with its σ-hole would show availability for halogen bonding. Both esters on the pyrazole ring engaged in hydrogen bonds forming dimers as depicted in the previous section. These

Compound 4.
For the compound 4, the intention was to insert, instead of the more bulky methyl group, a less sterically contributive group such as an ethyl group, which is more flexible. The Br atom was kept in the para position. Interestingly, compound 4 showed a similar pattern to compound 1 ( Figure 15).  One can observe the similarity of the C-I⋯O patterns in compounds 4 and 1 (A, B). The Br atom appears not to be involved in any interactions, although the distance Br⋯O (3.439 Å) between Br atom and -O-oxygen in the ester moiety attached to C-3 of the pyrazole ring is very close to the sum of the vdW radii. However, the angle C-Br⋯O of ~124° would not agree with the directionality of the halogen bond. As far as halogen bonding is concerned, the Hirshfeld analysis did not show any relevant contact for the Br atom, but only for the iodine atom. The similarity of the structural arrangements in the two compounds is depicted in Figure 16, showing the infinite C-I⋯O chains. Compound 5. By replacing the ethyl group with a very bulky isopropyl moiety, we could expect strong C-I⋯N interaction, as we had encountered with a previously reported compound [46] lacking the Br atom at the para position of the phenyl ring. However, the Br atom behavior in 5 ran contrary to expectations, and we observed instead a type II halogen-halogen interaction between the iodine One can observe the similarity of the C-I· · · O patterns in compounds 4 and 1 (A, B). The Br atom appears not to be involved in any interactions, although the distance Br· · · O (3.439 Å) between Br atom and -O-oxygen in the ester moiety attached to C-3 of the pyrazole ring is very close to the sum of the vdW radii. However, the angle C-Br· · · O of~124 • would not agree with the directionality of the halogen bond. As far as halogen bonding is concerned, the Hirshfeld analysis did not show any relevant contact for the Br atom, but only for the iodine atom. The similarity of the structural arrangements in the two compounds is depicted in Figure 16, showing the infinite C-I· · · O chains. One can observe the similarity of the C-I⋯O patterns in compounds 4 and 1 (A, B). The Br atom appears not to be involved in any interactions, although the distance Br⋯O (3.439 Å) between Br atom and -O-oxygen in the ester moiety attached to C-3 of the pyrazole ring is very close to the sum of the vdW radii. However, the angle C-Br⋯O of ~124° would not agree with the directionality of the halogen bond. As far as halogen bonding is concerned, the Hirshfeld analysis did not show any relevant contact for the Br atom, but only for the iodine atom. The similarity of the structural arrangements in the two compounds is depicted in Figure 16, showing the infinite C-I⋯O chains. Compound 5. By replacing the ethyl group with a very bulky isopropyl moiety, we could expect strong C-I⋯N interaction, as we had encountered with a previously reported compound [46] lacking the Br atom at the para position of the phenyl ring. However, the Br atom behavior in 5 ran contrary to expectations, and we observed instead a type II halogen-halogen interaction between the iodine Compound 5. By replacing the ethyl group with a very bulky isopropyl moiety, we could expect strong C-I· · · N interaction, as we had encountered with a previously reported compound [46] lacking the Br atom at the para position of the phenyl ring. However, the Br atom behavior in 5 ran contrary to expectations, and we observed instead a type II halogen-halogen interaction between the iodine atom of one molecule and the bromine atom of another molecule. In this case, iodine participated through its bigger sigma-hole, while the Br atom acted as the nucleophilic partner of the halogen bond. The type II halogen bond is also shown on the Hirshfeld surface at the correct positions (A, B). The bond distance and directionality of the short contact between the Br atom and the I atom are typical for a type II electrostatically driven halogen-halogen interaction ( Figure 17). As expected, the Hirshfeld surface shows also the red spots on the oxygen atoms in the esters which are involved in hydrogen bonds. Compound 6. The most interesting structure was obtained by replacing the ortho alkyl substituents with a chlorine atom. The small chlorine atom did not show potential for halogen bonding but instead formed C-H⋯Cl hydrogen bonds involving the methyl group of one ester moiety. This feature evidently rendered molecules of 6 unable to mimic the structural arrangements of the previously described compounds, and in fact, infinite anti-parallel chains of molecules held together via C-H⋯O bonds were formed instead.
These chains were linked by bifurcated iodine-nitrogen and iodine-oxygen bonds ( Figure  18A,B). The Hirshfeld surface depicts all the halogen contacts. Another unexpected but noteworthy observation was the occurrence of the C-Br⋯O interaction ( Figure 18C). Thus, apart from the interlayer C-H⋯Cl hydrogen bond made by the chlorine atom, we can conclude that in this case, the halogen bonding was clearly the driving force of the crystal packing. As expected, the Hirshfeld surface shows also the red spots on the oxygen atoms in the esters which are involved in hydrogen bonds. Compound 6. The most interesting structure was obtained by replacing the ortho alkyl substituents with a chlorine atom. The small chlorine atom did not show potential for halogen bonding but instead formed C-H· · · Cl hydrogen bonds involving the methyl group of one ester moiety. This feature evidently rendered molecules of 6 unable to mimic the structural arrangements of the previously described compounds, and in fact, infinite anti-parallel chains of molecules held together via C-H· · · O bonds were formed instead.
These chains were linked by bifurcated iodine-nitrogen and iodine-oxygen bonds ( Figure 18A,B). The Hirshfeld surface depicts all the halogen contacts. Another unexpected but noteworthy observation was the occurrence of the C-Br· · · O interaction ( Figure 18C). Thus, apart from the interlayer C-H· · · Cl hydrogen bond made by the chlorine atom, we can conclude that in this case, the halogen bonding was clearly the driving force of the crystal packing. The fingerprint plots (Table 2) show a summary of all the molecular interactions which were extracted from the Hirshfeld surface. They represent a "heatmap" of the frequencies of specific interactions between the atoms in the molecules. This suggests a more qualitative rather than a quantitative aspect of the interactions. The most frequent contacts are H⋯H accounting from 30%-40% of the total interactions. The I⋯O interactions account for the most frequent (5.5%) in compound 1 compared to 5, which presents the lowest I⋯O interactions (2%) (F 2-bar chart). Additionally, the gradient from blue to green on the fingerprint plot shows that in 1 not only the contact distances are small, but also the atoms share a greater percentage of the surface. Table S2 presents the fingerprint plots of the most relevant interactions. The fingerprint plots (Table 2) show a summary of all the molecular interactions which were extracted from the Hirshfeld surface. They represent a "heatmap" of the frequencies of specific interactions between the atoms in the molecules. This suggests a more qualitative rather than a quantitative aspect of the interactions. The most frequent contacts are H· · · H accounting from 30%-40% of the total interactions. The I· · · O interactions account for the most frequent (5.5%) in compound 1 compared to 5, which presents the lowest I· · · O interactions (2%) (F 2-bar chart). Additionally, the gradient from blue to green on the fingerprint plot shows that in 1 not only the contact distances are small, but also the atoms share a greater percentage of the surface. Table S2 presents the fingerprint plots of the most relevant interactions.  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and  Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I⋯C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and Hydrogen bonds are among the most important interactions, and they were rather frequent and presented a lower percentage only for compounds 1 and 4, which confirms the similarity of the two compounds, suggesting that not necessarily the Br atom but the ethyl group could be of greater importance in directing the crystalline growth, the less hindered rotation giving new possibilities of molecules to pack together.
An interesting outcome observed from the fingerprint plot was that compound 1 presented a similar percentage for the I· · · C interactions to compound 2 (4.9% vs. 4.7%). First, this may appear intriguing, but the Hirshfeld analysis in shape index mode could lead to the interpretation of an interaction between the lone pair electrons of the iodine atom and the pyrazole ring (Figure 19), although the contact distance was slightly higher than the sum of the vdW radii of the iodine and carbon atoms, and this was also the case for compound 4. The two compounds, 1 and 2, presented a similar degree of I· · · C interactions to that in compound 3, and the presence of such interactions even in a low percentage highlights the role of the bulky iodine atom in stabilizing the crystal packing.
Crystals 2020, 10, x FOR PEER REVIEW 17 of 22 carbon atoms, and this was also the case for compound 4. The two compounds, 1 and 2, presented a similar degree of I⋯C interactions to that in compound 3, and the presence of such interactions even in a low percentage highlights the role of the bulky iodine atom in stabilizing the crystal packing.

Quantum Computations
The magnitude of the σ-holes for the halogen atoms was measured for the compounds 1-6 using G09 program suite [59], having as starting point the structures obtained by single crystal X-ray diffraction. Due to the fact that the hydrogen atoms were not located accurately by X-ray diffraction, their position was optimized at the B3LYP-D3/dgdzvp level [60,61] with the vdW dispersion correction [62]. The DGDZVP basis set is sufficiently accurate for all atomic species, without the need for any pseudopotential [63]. The electrostatic potential V(r) created by the electrons and nuclei of the atoms at any point r was proven to be an accurate approach for the interpretation and quantification of the non-covalent interactions. For this reason, the V(r) was generated on the molecular surface, defined as 0.001 e Bohr −3 (a. u.) contour of the electronic density. This is a low electron density envelope generated in the range of the atomic vdW radii, defined by Bader et al. to be meaningful for non-covalent interactions [60]. Electrostatic surface potential (ESP) was evaluated using the B3LYP-D3/def2tzvp basis set [64]. The maximum values of the electronic potential on the halogen atom (local maximum) are referred to as Vs,max [34,37]. Table 3 presents the ESPs of compounds 1-6 rendered in the interval −0.001 and +0.001 a.u. and the corresponding values of Vs,max which represent the maximum value on the halogen atom σ-hole.

Quantum Computations
The magnitude of the σ-holes for the halogen atoms was measured for the compounds 1-6 using G09 program suite [59], having as starting point the structures obtained by single crystal X-ray diffraction. Due to the fact that the hydrogen atoms were not located accurately by X-ray diffraction, their position was optimized at the B3LYP-D3/dgdzvp level [60,61] with the vdW dispersion correction [62]. The DGDZVP basis set is sufficiently accurate for all atomic species, without the need for any pseudopotential [63]. The electrostatic potential V(r) created by the electrons and nuclei of the atoms at any point r was proven to be an accurate approach for the interpretation and quantification of the non-covalent interactions. For this reason, the V(r) was generated on the molecular surface, defined as 0.001 e Bohr −3 (a. u.) contour of the electronic density. This is a low electron density envelope generated in the range of the atomic vdW radii, defined by Bader et al. to be meaningful for non-covalent interactions [60]. Electrostatic surface potential (ESP) was evaluated using the B3LYP-D3/def2tzvp basis set [64]. The maximum values of the electronic potential on the halogen atom (local maximum) are referred to as V s,max [34,37]. Table 3 presents the ESPs of compounds 1-6 rendered in the interval −0.001 and +0.001 a.u. and the corresponding values of Vs,max which represent the maximum value on the halogen atom σ-hole.
The molecules 1-6 presented relatively similar values for the σ-hole V s,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller V s,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the V s,max value. However, it seems that the chlorine atom influenced the V s,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment. Table 3. The electrostatic surface potential (ESP) of 1-6, mapped over 0.001 a.u. showing the σ-hole of the iodine and bromine atoms.
Front view of I atom along I-C bond quantification of the non-covalent interactions. For this reason, the V(r) was generated on the molecular surface, defined as 0.001 e Bohr −3 (a. u.) contour of the electronic density. This is a low electron density envelope generated in the range of the atomic vdW radii, defined by Bader et al. to be meaningful for non-covalent interactions [60]. Electrostatic surface potential (ESP) was evaluated using the B3LYP-D3/def2tzvp basis set [64]. The maximum values of the electronic potential on the halogen atom (local maximum) are referred to as Vs,max [34,37]. Table 3 presents the ESPs of compounds 1-6 rendered in the interval −0.001 and +0.001 a.u. and the corresponding values of Vs,max which represent the maximum value on the halogen atom σ-hole. quantification of the non-covalent interactions. For this reason, the V(r) was generated on the molecular surface, defined as 0.001 e Bohr −3 (a. u.) contour of the electronic density. This is a low electron density envelope generated in the range of the atomic vdW radii, defined by Bader et al. to be meaningful for non-covalent interactions [60]. Electrostatic surface potential (ESP) was evaluated using the B3LYP-D3/def2tzvp basis set [64]. The maximum values of the electronic potential on the halogen atom (local maximum) are referred to as Vs,max [34,37]. Table 3 presents the ESPs of compounds 1-6 rendered in the interval −0.001 and +0.001 a.u. and the corresponding values of Vs,max which represent the maximum value on the halogen atom σ-hole. quantification of the non-covalent interactions. For this reason, the V(r) was generated on the molecular surface, defined as 0.001 e Bohr −3 (a. u.) contour of the electronic density. This is a low electron density envelope generated in the range of the atomic vdW radii, defined by Bader et al. to be meaningful for non-covalent interactions [60]. Electrostatic surface potential (ESP) was evaluated using the B3LYP-D3/def2tzvp basis set [64]. The maximum values of the electronic potential on the halogen atom (local maximum) are referred to as Vs,max [34,37]. Table 3 presents the ESPs of compounds 1-6 rendered in the interval −0.001 and +0.001 a.u. and the corresponding values of Vs,max which represent the maximum value on the halogen atom σ-hole. quantification of the non-covalent interactions. For this reason, the V(r) was generated on the molecular surface, defined as 0.001 e Bohr −3 (a. u.) contour of the electronic density. This is a low electron density envelope generated in the range of the atomic vdW radii, defined by Bader et al. to be meaningful for non-covalent interactions [60]. Electrostatic surface potential (ESP) was evaluated using the B3LYP-D3/def2tzvp basis set [64]. The maximum values of the electronic potential on the halogen atom (local maximum) are referred to as Vs,max [34,37]. Table 3 presents the ESPs of compounds 1-6 rendered in the interval −0.001 and +0.001 a.u. and the corresponding values of Vs,max which represent the maximum value on the halogen atom σ-hole. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where E dimer, E monomer1 , E monomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory. The molecules 1-6 presented relatively similar values for the σ-hole Vs,max magnitudes which could be categorized as medium to high, giving to these compounds high XB donor affinity comparable to the σ-hole of iodobenzimidazoles and other arylpyrazoles for which similar halogen bonding models were encountered [46,65]. The compounds 1 and 2 lacking a withdrawing group/atom on the aryl ring, had a smaller Vs,max compared to the compounds that had a Br atom at the para position on the aryl fragment. Therefore, the electron withdrawing substituent showed some influence on the positive magnitude of the iodine σ-hole which was placed at a relatively large distance from the iodine atom, although through conjugation, it can influence it. On the other hand, the Cl atom from structure 6 placed on the same aryl ring in the meta position with respect to the Br atom seemed to show no contribution in increasing the Vs,max value. However, it seems that the chlorine atom influenced the Vs,max of the Br atom compared to the alkyl substituents, this being the largest among all the four compounds bearing a Br atom attached to the aryl fragment.
The interaction energies between the molecules involved in halogen bonds (Table 4) were calculated at the same level of theory as for the ESP contours, according to the classical formula: where Edimer, Emonomer1, Emonomer2 are the DFT energies calculated at the B3LYPD3/Def2tzvp level, and BSSE is the correction calculated at the same level of theory.  Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I⋯O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I⋯O intermolecular bond strengths) were of the following types and strengths: C-I⋯Br of 5-1 (−18.96 kJ/mole), C-Br⋯O of 3-2 (−19.31 kJ/mole) and C-Br⋯O of dimer2 of 6 (−13.63 kJ/mole). The C-I⋯π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I⋯O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H⋯O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I⋯O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I⋯O intermolecular bond strengths) were of the following types and strengths: C-I⋯Br of 5-1 (−18.96 kJ/mole), C-Br⋯O of 3-2 (−19.31 kJ/mole) and C-Br⋯O of dimer2 of 6 (−13.63 kJ/mole). The C-I⋯π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I⋯O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H⋯O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I⋯O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I⋯O intermolecular bond strengths) were of the following types and strengths: C-I⋯Br of 5-1 (−18.96 kJ/mole), C-Br⋯O of 3-2 (−19.31 kJ/mole) and C-Br⋯O of dimer2 of 6 (−13.63 kJ/mole). The C-I⋯π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I⋯O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H⋯O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I⋯O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I⋯O intermolecular bond strengths) were of the following types and strengths: C-I⋯Br of 5-1 (−18.96 kJ/mole), C-Br⋯O of 3-2 (−19.31 kJ/mole) and C-Br⋯O of dimer2 of 6 (−13.63 kJ/mole). The C-I⋯π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I⋯O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H⋯O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I⋯O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I⋯O intermolecular bond strengths) were of the following types and strengths: C-I⋯Br of 5-1 (−18.96 kJ/mole), C-Br⋯O of 3-2 (−19.31 kJ/mole) and C-Br⋯O of dimer2 of 6 (−13.63 kJ/mole). The C-I⋯π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I⋯O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H⋯O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I⋯O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I⋯O intermolecular bond strengths) were of the following types and strengths: C-I⋯Br of 5-1 (−18.96 kJ/mole), C-Br⋯O of 3-2 (−19.31 kJ/mole) and C-Br⋯O of dimer2 of 6 (−13.63 kJ/mole). The C-I⋯π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I⋯O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H⋯O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in 6-1 −43.14 kJ/mol 6-2 −13.63 kJ/mol Analyzing the theoretical interaction energies, the trends varied linearly with the values of the σ-hole strength (iodine gave stronger interactions than bromine due to the smaller electropositive value of the Br σ-hole). Therefore, the strongest interactions were of the type C-I· · · O with ≈32 kJ/mole in 1-1 and 4-1. Much weaker interactions (almost half of the halogen I· · · O intermolecular bond strengths) were of the following types and strengths: C-I· · · Br of 5-1 (−18.96 kJ/mole), C-Br· · · O of 3-2 (−19.31 kJ/mole) and C-Br· · · O of dimer2 of 6 (−13.63 kJ/mole). The C-I· · · π interaction in the 2-1 structure was also weaker (−18.05 kJ/mole) than C-I· · · O because of the lower electronegativity of the π-electron cloud. On the other hand, in addition to the halogen bonds, hydrogen bonds remain important interactions and, for comparison, values of their interaction energies were calculated in 1S and 5S (Table S3). For example, for the interaction energies in the dimers 1S and 5S generated by hydrogen bonds, the interaction energy values were −27.45 and −18.29 kJ/mole (for one single C-H· · · O interaction), thus making the values of the energy interactions in the case of halogen bonds to be considered rather strong.

Conclusions
In conclusion, we have shown that halogenated 1-phenylpyrazoles present interesting features regarding the halogen bond, which can be further evaluated to gain more insight into the predictability of the halogen bond. Six crystals were investigated and showed different halogen bond patterns. The halogen contacts presented strong similarity with the literature regarding contact distances and directionality. Furthermore, by introducing a Br atom on the phenyl ring, it was shown that it too could be involved in halogen bonding. Iodinated pyrazoles are important benchmarks in investigating the nature of the halogen bond and could also lead to a deeper understanding of halogen bonding of analogous residues in macromolecules.