Halogen bonds versus hydrogen bonds in the crystal packing formation of halogen substituted anilines

2.1 Quantum chemical calculations

All the studied structures had been retrieved from the Cambridge Structural Database (release 2024). ¹¹ The analysis of the studied structures was performed using the approach based on calculations of pairwise interaction energies between molecules in a crystal. ^{22 , 23 , 24} The first coordination sphere for each molecule found in the unit cell asymmetric part (M ₀ ) was determined separately using the standard procedure within the Mercury program (version 4.2) ²⁵ as had been suggested before. ²³ The obtained cluster was divided into dimers where one molecule is M ₀ and every other molecule M _i belongs to the first coordination sphere. The atomic coordinates of M₀-M_i dimers were taken from the X-ray diffraction data excluding the positions of hydrogen atoms, which were normalized to 1.089 Å for C–H and 1.015 Å for N–H bonds according to the results of the geometry optimization of the isolated molecule. Such a normalization of the hydrogen atoms positions is needed due to the well-known fact that the X–H bonds determined by X-ray diffraction study are shortened. ²⁶

The interaction energies between molecules within each of M ₀ −M _i dimers were calculated using B97-D3/Def2-TZVP density functional method ^{27 , 28 , 29 , 30 , 31} and corrected for basis set superposition error by the counterpoise method. ³² The B97-D3 functional was benchmarked to be one of the most powerful dispersion-corrected density functionals for the calculations of various intermolecular interactions. ³³ All the calculations were performed with the ORCA 5.0 software. ³⁴

The analysis of the pairwise interaction energies is based on the assumption that the calculated values take on vector properties, ²³ because each calculated interaction energy originates from the geometric center of the basic molecule M ₀ and is directed to one of the neighboring molecules M _i . All the energy vector lengths within the first coordination sphere of the basic molecule are normalized to the strongest pairwise interaction energy using the equation:

where R _i is the distance between the geometrical centers of interacting molecules M ₀ −M _i , E _i is the interaction energy between two molecules in these pairs and E _str is the energy of the strongest pairwise interaction in the crystal structure.

Such a normalization results in the independence of the vector lengths from the calculation method. Application of this approach makes it possible to replace the basic molecule by its vector image and to construct the so-called energy-vector diagram of a crystal structure using symmetry operations.

3.1 Molecular structure analysis

The ability of the amino group to engage in intermolecular interactions as either a proton donor and/or a proton acceptor is highly influenced by the extent of n−π conjugation between the nitrogen lone pair and the aromatic π-system. It is well established that the degree of this conjugation is affected by the surrounding polarizing environment. ^{22 , 35 , 36} The primary indicators of the conjugation degree are the C–N bond length and the geometrical configuration of the nitrogen atom. When the conjugation is strong, the C–N bond length is shorter than expected for the formal valence. In this case the nitrogen atom adopts a planar configuration, with respect of the attached ring carbon atom and the two hydrogen atoms.

The analysis of the molecular structures revealed that the C–NH₂ bond lengths vary within the range of 1.375–1.400 Å, and the sums of bond angles centered at the nitrogen atom range from 328.7° to 360° in 1–6 (Table 2). This variation indicates that the degree of conjugation between the amino group and the aromatic ring spans a wide range, depending on the position and type of substituent. This general tendency is similar to that what has been previously reported for some aminopyridines. ³⁷

The iodine-substituted anilines 3 and 6 show the weakest conjugation with the aromatic π-system. This is confirmed by the C_ar–N bond lengths (Table 2) and the nearly planar configuration of the nitrogen atoms. The strongest conjugation is observed in ortho-chloroaniline 4 (Table 2). As a result, we can expect the formation of hydrogen bonds involving the amino group as a proton acceptor with greater probability in the crystals of iodine-substituted anilines, because of the stronger sp ³ character of the nitrogen, with the lone pair predesigned to accept for example one classical hydrogen bond.

It should be noted that the method of X-ray diffraction has some limitations in determining and refining hydrogen atom positions. Depending on the quality of the experiment and the investigated single crystal, the positions of hydrogen atoms can be obtained from experimental data or have to be calculated geometrically. The refinement method is another possibility for ambiguity in determining the positions of hydrogen atoms. High-quality experimental data allow the refining of hydrogen atoms using isotropic approximations. In this case, the configuration of the nitrogen atom is determined unambiguously, and the geometric characteristics of the amino group can be analyzed based on X-ray diffraction data. However, insufficient experimental quality necessitates refining hydrogen atoms using the “riding” model, which imposes limitations on the X–H bond lengths and the true orientation of hydrogen atoms. The application of such a model most often results in a planar configuration of the nitrogen atom. Therefore, this feature must be taken into account when analyzing the molecular structure of compounds obtained from the literature and the Cambridge Structural Database. ¹¹ In the case of the deposited structure of 4 the hydrogen atoms were added using the “riding” model that leads to a planar configuration of the nitrogen atom. In this case, we cannot find objective conclusions regarding the configuration of the amino group and its participation as a proton acceptor in hydrogen bonds.

It should be mentioned that geometrical characteristics of amino groups, such as the X–NH₂ bond length also depend on the intermolecular interactions formation. Therefore, a quantitative analysis of intermolecular interactions has been investigated.

3.2 Crystal structure analysis of compounds 1–6 based on studying of geometrical characteristics of intermolecular interactions

The presence of a halogen atom as in the para-substituent of an aniline lead to the expectation of halogen bonds (X-bonds) and hydrogen bonds (H-bonds) involving the halogen as a proton acceptor.

As expected for the para-chloro- and para-bromoaniline, we observed C/N–H⋯Hal and Hal⋯π intermolecular interactions with similar geometric parameters, indicating the relatively weak nature of these interactions (Table 3). Also as expected from geometrical amino group characteristics, only in the crystal structure of 3 N–H⋯NH₂ hydrogen bonding was observed (Table 3). Moreover, weak C/N–H⋯π and N–H⋯I hydrogen bonds as well as I⋯I halogen bond at the same time have been revealed only in the crystals of 3.

Table 3:

Intermolecular interactions and their geometric characteristics in the crystals of compounds 1–3.

Compound	Interaction	Symmetry operation	Н…А, Å	D–Н…А, deg.
1	C2–H2⋯Cl1	1/2 − x, −y, −1/2 + z	2.89	152
	N1–H1N⋯Cl1	1/2 − x, −y, −1/2 + z	2.98	143
	Cl1⋯π	1/2 + x, 1/2 − y, 3/2 − z	3.48	175
2	C2–H2⋯Br1	3/2 − x, 1 − y, −1/2 + z	3.01	154
	N1–H1N⋯Br1	3/2 − x, 1 − y, −1/2 + z	3.12	148
	Br1⋯π	−1/2 + x, 1/2 − y, 3/2 − z	3.46	176
3	N1–H1N⋯N1LP	2 − x, 1/2 + y, 1 − z	2.30	162
	N1–H1N⋯π	1 + x, 1 + y, z	2.87	134
	C5–H5⋯π	1 − x, 1/2 + y, −z	2.76	169
	N1–H1N⋯I1	1 − x, 2 − y, −0.5 + z	3.22	135
	I1⋯I1	−x, −1/2 + y, −z	4.03	154

According to the geometrical characteristics, the molecules in 1 form only weak intermolecular interactions (Table 3, Figure 1a). As a result, zig-zag chains are recognized as a main packing motif in the crystal structure of 1 (Figure 1b).

Figure 1:

Packing of molecules 1 in the crystalline phase: (a) intermolecular interactions; (b) zig-zag chains, projection along the crystallographic b direction. Green: chlorine, blue: nitrogen.

Dey and co-workers have already noted that 4-chloroaniline is isostructural with 4-bromoaniline. ¹⁶ Moreover, according to visual analysis of crystal packings and geometrical characteristics isostructurality of these compounds is obvious (Figures 1 and 2, Table 3).

Figure 2:

Packing of molecules 2 in the crystalline phase: (a) intermolecular interactions; (b) zig-zag chains, projection along the b crystallographic direction. Brown: bromine, blue: nitrogen.

In the crystals of 3 the strongest intermolecular interaction due to the geometric characteristics is N1–H1N⋯N1_LP hydrogen bond where the amino group acts simultaneously as proton donor and proton acceptor (Figure 3a). This interaction is found only in the crystals of 3 (from para-substituted aminoanilines). As mentioned above the longer C–N bond and the sp ³-hybridization of the amino group (Table 2) indicate a very weak n-π conjugation in molecule 3 that makes it possible to form the N–H⋯N_LP hydrogen bond (Table 3). In this situation only one hydrogen atom forms a classical hydrogen bond, whereas the other is inactive, probably due to sterical reasons. In result, the molecules of 3 form zig-zag chains along the crystallographic c-direction due to formation of N–H⋯N_LP hydrogen bonds (Figure 3b). Furthermore, the I⋯I halogen bonds as well as C/N–H⋯π weak interactions connect neighboring chains. The diversity of these interactions makes it difficult to compare them and separate out the one which is the most important (Figure 2c).

Figure 3:

Packing of molecules 3 in the crystalline phase: (a) a N–H…N_LP dimer; (b) a zigzag chain along the c crystallographic direction; (c) the crystal structure, projection along the a crystallographic direction. Violet: iodine, blue: nitrogen.

The presence of the halogen atom in ortho-position in the molecules of 4–6 leads to an increase in the number of intermolecular interactions. As a result, N–H⋯N_LP hydrogen bonds – where the amino group acts simultaneously as a proton donor and acceptor – were observed, along with Hal⋯Hal halogen bonds (XB), across all structures 4–6 (Table 4). The types and geometric characteristics of these interactions are quite similar. However, comparing the strength of these interactions is somewhat complicated due to the variation in van der Waals radii for halogen atoms across different sources. For example, Zefirov’s parameters provide longer van der Waals radii compared to classical Bondi’s parameters. In 2014, Hu et al. systematically compared and calculated average van der Waals values for halogen atoms based on various approaches. ³⁸ According to these averages, the Cl⋯Cl halogen bond is about 2.5 % outside the range (average value: 3.58 Å), the Br⋯Br bond is 6 % shorter than the average (3.86 Å), and the I⋯I bond is 12 % shorter than the average (4.24 Å) in the 4–6 crystals. This suggests that, based on its geometric characteristics, that the I⋯I halogen bond in the crystal of 6 is the strongest halogen bond among these structures (Table 4).

Table 4:

Intermolecular interactions and their geometric characteristics in the crystals of compounds 4–6.

Compound	Interaction	Symmetry operation	Н…А, Å	D-Н…А, deg.
4	N1–H1N⋯N1LP	2 − y, 1 + x − y, 1/3 + z	2.35	171
	C6–H6⋯Cl1	2 − y, 1 + x − y, 1/3 + z	3.01	168
	N1–H2N⋯С6π	2 − y, 1 + x − y, −2/3 + z	2.74	131
	C5–H5⋯С3π	1 − y, 1 + x − y, 1/3 + z	2.83	142
	Cl1⋯Cl1	2 − y, 2 + x − y, −2/3 + z	3.67	168
	C1⋯C4	x, y, −1 + z	3.49
5	N1–H1N⋯N1LP	−x + y, x, −1/3 + z	2.34	164
	C6–H6⋯Br1	−x + y, x, −1/3 + z	2.98	169
	N1–H2N⋯С6π	−x + y, −x, 2/3 + z	2.91	121
	C5–H5⋯С3π	−y, −1 + x − y, 1/3 + z	2.93	131
	Br1⋯Br1	−y, x − y, 1/3 + z	3.64	170
	C1⋯C4	x, y, 1 + z	3.42
6	N1–H1N⋯N1LP	0.5 − x, −0.5 + y, 0.5 + z	2.31	158
	C6–H6⋯I1	0.5 − x, −0.5 + y, −0.5 + z	3.17	161
	N1–H2N⋯С6π	0.5 − x, −0.5 + y, −0.5 + z	2.84	127
	C5–H5⋯С3π	1 − x, 2 − y, −0.5 + z	2.86	135
	I1⋯I1	−y, x − y, −1/3 + z	3.80	173
	C1⋯C4	x, −1 + y, z	3.41

The analysis of possible intermolecular interactions in crystals 4–6 revealed that the amino group forms one hydrogen bond simultaneously acts as proton donor as well as proton acceptor and one hydrogen bond only as proton acceptor. Halogen atoms participate in intermolecular interactions and form Hal⋯Hal halogen bonds and a non-classical C6–H6⋯Hal hydrogen bonds. Additionally, the weak C5–H5⋯π hydrogen bonds were revealed (Table 4). Taking into account that the N–H⋯N_LP hydrogen bond looks to be the strongest in crystals 4–6, the triple columns along the c crystallographic direction may be separated out (Figures 4 and 5). The molecules inside columns are bound by N1–H1N⋯N_LP, N1–H2N⋯π and C6–H6⋯Hal interactions (Figure 4). Neighboring columns are furthermore connected by Hal⋯Hal and C5–H5⋯π bonds.

Figure 4:

Triple column as structural motif in the crystals 4–6.

Figure 5:

Packing of molecules 4–6 in the crystalline phase. Projection along the с crystallographic direction.

It should be noted that stacking interactions are completely absent in the structures of para-substituted halogen anilines despite the presence of the aromatic π-system (Table 3). Similar absences of any stacking interactions were indicated in the crystals of all the isomers of diaminobenzenes and mono-aminopyridines. ^{37 , 39} However, in ortho-substituted halogen anilines 4–6 the stacking interactions were observed (Table 4, Figure 5), that show a different shift to next π-system (see Figure 6). Stacking interactions also significantly participate in the formation of triple columns.

Figure 6:

The stacking interactions in the crystals 4–6.

From a geometric perspective, the summarized results of the crystal structure study allow us to conclude:

1. The amino group in para-halogen anilines 1–2 participates in hydrogen bonding mainly as a proton donor;

2. Stacking interactions are absent in structures 1–3;

3. In compounds 3–6, the amino group simultaneously acts as both a proton donor and a proton acceptor in hydrogen bonding;

4. Analyzing only the geometric characteristics of intermolecular interactions does not permit definitive conclusions regarding certain structural motifs in crystal packing and seriously underestimates the role of weak interactions in crystal structure formation.

3.3 Crystal structure analysis of compounds 1–6 based on an energetic viewpoint

As mentioned earlier, analyzing geometric characteristics is not always the most effective approach for studying the peculiarities of crystal packing when multiple weak interactions are present. A more efficient method is the analysis of interaction energies between neighboring molecules, calculated using ab initio methods. ^{22 , 23 , 24 , 37 , 39} The key advantage of this approach is its independence from the specific nature of the interactions, while accounting for all existing interactions (such as hydrogen bonding, dispersion, electrostatic interactions, polarization, etc.). Additionally, this method can be applied not only to individual molecules as simple building units (BU) of a crystal packing but also to more complex BUs like dimers, trimers, or tetramers of molecules. ²³

The first coordination sphere for each of the building units (molecule or dimer) which is located in the asymmetric part of the unit cell across all studied crystals contains 12–14 neighboring units. The complete list of symmetry operations and interaction energies for the corresponding dimers can be found in the Electronic Supplementary Information (ESI) (Tables S1–S6). Selected data for the dimers, where the interaction energies are stronger than 5 % of the total interaction energy of the basic molecule with all molecules in its first coordination sphere, are presented in Tables 5–10.

The total interaction energy of the basic molecule 1 with the 14 crystallographically dependent molecules in its first coordination sphere is −46.6 kcal/mol. Analysis of pairwise interaction energies shows that the molecule in 1 forms two of its strongest interactions (non-specific) with molecules located in opposite directions (Table 5, Figure 7a). These interactions have identical energies of −5.35 kcal/mol each, forming a zig-zag column, which can be identified as the primary basic structural motif (BSM) in the crystal of 1 (Figure 7c). The bond angle formed by the geometric centers of the basic molecule and its strongly bound neighboring molecules is 90.4°. The total interaction energy of molecules in 1 within this column is −10.7 kcal/mol. The interaction energy between neighboring columns is weaker, ranging from −3.2 to −4.7 kcal/mol, and is primarily supported by C/N–H⋯Cl and C–H⋯N hydrogen bonds, as observed in the 1-d3 dimer (Figure 7b). Additionally, Cl⋯π interactions and other non-specific interactions also contribute to the overall stability of these neighboring columns. Thus, the crystal of 1 has only one level of organization and must be classified as columnar (Figure 7d).

Figure 7:

The1-d1dimer with the strongest interaction in structure 1 (a), the 1-d3 dimer (b), zig-zag column (c), packing in terms of energy-vector diagrams, projection along the c crystallographic direction (d).

The total interaction energy of the basic molecule 2 with the 12 molecules in its first coordination sphere is −37.0 kcal/mol. The crystal structure of 2 exhibits a supramolecular architecture similar to that of crystal 1. Like the molecules in 1, the molecules in 2 form its two strongest interactions (non-specific) with molecules positioned in opposite directions (Table 6, Figure 8a). These interactions have identical energies of −5.08 kcal/mol each, creating a zig-zag column, which can be identified as the primary BSM in the crystal of 2 (Figure 8b). Similar to the structure of compound 1, the basic molecules in the structure 2 also form an orthogonal arrangement with their strongly bound neighbors. The valence angle, formed by the geometric center of the basic molecule as a vertex and the geometric centers of the neighboring molecules within the column, is 93.5° (Figure 8). The total interaction energy within this column is −10.2 kcal/mol. The interaction energy between neighboring columns is weaker, ranging from −3.2 to −4.7 kcal/mol, and is primarily stabilized by C/N–H⋯Br hydrogen bonds, along with Br⋯π and other non-specific interactions. Thus, we can sum up that the crystal of compound 2 also exhibits a single level of organization and can be classified as columnar (Figure 8d).

Figure 8:

The 2-d1 dimer with the strongest interaction in structure 2 (a), zig-zag column (b), packing in terms of energy-vector diagrams, projection along the c crystallographic direction (c).

Similar to structure 1 the first coordination sphere of the basic molecule in structure 3 contains 14 neighboring molecules. The total interaction energy of the basic molecule with all the surrounding ones is −50.0 kcal/mol. As well as in the previous structures the analysis of pairwise interaction energy revealed that the basic molecule 3 forms two identical interactions with the highest energy (Table 7, Figure 9a). In contrast to the single column in the structures of 1 and 2 the molecules of compound 3 form a double zig-zag column as the primary BSM (Figure 9c). The molecules within the column are bound by the C–H⋯π hydrogen bonds and π⋯π interactions (Figure 9a and b). The interaction energy of the basic molecule with its neighbors within the column is −23.1 kcal/mol, which is more than twice as high as the interaction energy within the zig-zag columns in structures 1 and 2. It should be noted that the bond angle within the zig-zag column differ from structures 1 and 2 and it is more acute (55.5°). The neighboring columns are bonded mainly due to the N–H⋯N(H₂) hydrogen bonds and some non-specific interactions. The interactions of the primary BSM with neighboring columns are several times weaker (−5.4 ÷ −8.7 kcal/mol) than the interaction energy within the column (Figure 9d). As a result, the crystal structure of compound 3 can be also classified as columnar.

Figure 9:

The 3-d1 dimer with the strongest interaction in structure 3 (a), the 3-d3 dimer (b), zig-zag column (с), packing in terms of energy-vector diagrams, projection along the b crystallographic direction (d). The double columns are highlighted green.

It should here be mentioned that the crystal packing principles of para-chloro and para-bromo anilines are similar, sharing the same supramolecular architectures and structural motifs. However, the crystal packing of the para-iodo substituted aniline differs, indicating that the larger size and the somehow different electronic properties of the iodine atom significantly influence the overall packing arrangement and interactions in this crystal structure.

The basic molecule in 4 is surrounded by 12 neighboring molecules, similar to the arrangement in structure 2, with a total interaction energy of −35.5 kcal/mol. Also in this case, the analysis of pairwise interaction energies reveals that basic molecule 4 forms two stacking interactions with the highest energies (Table 8, Figure 10a). Instead of zig-zag columns in structures 1–3, the molecules strongly bound to basic molecule 4 create a straight stacking column (Figure 10b). The interaction energy within single column is −9.4 kcal/mol.

Figure 10:

The stacking dimer with the strongest interaction in structure 4 (a), a stacking column (b), packing in terms of energy-vector diagrams, projection along the c crystallographic direction (c). The triple columns are highlighted pink.

The column is strongly bound with two other columns mainly by classical N–H⋯N_LP, N–H⋯π and C–H⋯Cl hydrogen bonds. In result, the triple column can be recognized as the primary basic structural motif (BSM1) in the crystal of 4 (Figure 10c). The interaction energy within the triple column is −23.4 kcal/mol. The interaction energy between the neighboring triple columns is only twice as small as the interaction energy within the triple column (−12.2 kcal/mol) and is provided by weak С–Н⋯π, non-specific and Cl⋯Cl interactions. Thus, the structure 4 also can be classified as a columnar arrangement.

Similar to structures 1 and 3 the construction of the first coordination sphere for the basic molecule 5 revealed 14 neighboring units. However, the total interaction energy of the basic molecule with its neighbors is smaller (−42.9 kcal/mol). It is caused by smaller interaction energies of all interactions in the crystal 5 (Table 9).

A detailed analysis of the pairwise interaction energies in structure 5 reveals that the basic molecule forms its two strongest interactions with neighboring molecules, which are aligned on a straight line due to stacking interactions (Table 9, Figure 11a). The stacking dimers 5-d1 and 5-d2 exhibit stronger interaction energies than those in the structure 4. Similar to the crystal structure 4, a triple column can be identified as the primary basic structural motif in the crystal of 5 (Figure 11b). The interaction energy of the basic molecule within this triple column is −28.6 kcal/mol, driven by N–H⋯N_LP, N–H⋯π and C–H⋯Br hydrogen bonds. Neighboring triple columns are connected by weaker C–H⋯π, N–H⋯π, non-specific, and Br⋯Br halogen bond interactions. The interaction energy between these neighboring triple columns is −14.3 kcal/mol. Therefore, the crystal structure of 5 has only one level of organization and can be classified as columnar (Figure 11c).

Figure 11:

The stacking dimer with the strongest interaction in structure 5 (a), a triple column (b), packing in terms of energy-vector diagrams, projection along the c crystallographic direction (c). The triple columns are highlighted blue.

Similar to structures 1, 3, and 5, the first coordination sphere for the basic molecule in structure 6 includes 14 neighboring molecules. The total interaction energy of the basic molecule with its neighbors is slightly smaller than in structures 1 and 5, but a bit larger than in structure 4, totaling −46.2 kcal/mol. The strongest interactions in structure 6 are also stacking interactions, as observed in crystals 4 and 5 (Table 10, Figure 12a). However, in the crystal of structure 6, the stacking interactions have the lowest interaction energies compared to the other structures.

Figure 12:

The stacking dimer with the strongest interaction in structure 6 (a), a triple column (b), packing in terms of energy-vector diagrams, projection along the c crystallographic direction (c). The triple columns are highlighted in pink.

Moreover, these stacking interactions play a crucial role in the organization of the crystal structure, forming stacking columns. These columns are connected into triple columns via N–H⋯N_LP, N–H⋯π, and C–H⋯I hydrogen bonds. The interaction energy of the basic molecule within the column is −29.7 kcal/mol. Molecules from neighboring columns are primarily bound by weaker C–H⋯π and N–H⋯π hydrogen bonds, some weak I⋯I halogen bonds, and also some non-specific interactions (Table 11).