Supramolecular Switching by Substituent Tuning: A Crystal Engineering Study of 2-Amino- and 2,3-Diamino-5-Halogenopyridines

Abstract

The crystal structures of the 2-amino-5-halogenopyridines (halogen = Cl (1), Br (2)) and 2,3-diamino-5-halogenopyridines (halogen = Cl (3), Br (4)) were compared with respect to their intermolecular interactions. An ab-initio-based method for evaluating the interaction energies between molecules was employed to estimate the driving forces of crystal formation. As a result, regularities in crystal structure organization were identified. For compounds 1 and 2, a dimeric building unit is formed by two N–H…N_pyr hydrogen bonds. These dimers are further connected to neighboring units by C–H…π, C–H…N, N…X (X = Cl, Br), and non-specific interactions. The aforementioned intermolecular interactions give rise to layered structures that are similar but not isotypical. No significant contributions from π–π or N–H…N(H₂) interactions are observed in 1 and 2. The structures of 3 and 4 are isotypical and crystallize in the non-centrosymmetric space group P2₁2₁2₁. The most important intermolecular interactions are N–H…N_pyr, N–H…N(H₂), and stacking interactions. These interactions lead to identical columnar-layered structures in both 3 and 4. No significant contributions from halogen bonds of the type N…X (X = Cl, Br) are found in 3 and 4.

1. Introduction

The formation of diverse crystal packing motifs arises from a molecule’s ability to engage in specific and non-specific intermolecular interactions [1], driven by its functional groups. Understanding the interactions of the molecular functional groups and the molecule as a whole is the key to the design of supramolecular synthons for crystal engineering [2,3,4]. According to this concept, molecules containing substituents that may form directional interactions like hydrogen bonds first of all form common motifs in the crystal phase by a standard set of medium-strong to strong intermolecular interactions [5,6]. Hence, modulating the capacity of a molecule to create specific intermolecular interactions represents an effective approach for designing the supramolecular architecture of crystal structures. A class of compounds that has been in the focus of research for many years are aminopyridines [7,8]. Recently we investigated some halogenoanilines by aforementioned methods [9,10]. In general, the establishment of another amino group at benzene/pyridine cores results in some diversification of intermolecular interaction possibilities due to the large variety of functional groups. In detail, the title compounds are able to form more and more complex N–H…π, N–H…N, and C–H…N interactions in the solid state. The bifunctional character of the amino group is well known. It originates from the conjugation degree between the nitrogen lone pair and π-system of the benzene cycle. As a result, the acceptor properties of the amino group are strong enough for N–H…N intermolecular hydrogen bonds. The role of N–H…N interactions in the crystal structure in halogenoaminopyridines and halogenodiaminoanilines strongly depends on the position of the amino and the halogen group in the cycle, respectively. The principles of construction of the corresponding crystal are more complicated to understand if a halogen substituent is present in amino- [11] and diaminobenzene, respectively [12]. The same holds true for protonated aminopyridines that even face tautomerization upon protonation at the N atom of the pyridyl ring [13].

Aminopyridines represent essential structural scaffolds found in a wide range of bioactive natural products, pharmacologically significant compounds, and advanced functional organic materials. Their versatile chemical reactivity and biological relevance have made them valuable targets in synthetic and medicinal chemistry [14,15,16,17]. Given this significance, it is reasonable to anticipate that halogenated derivatives of these diaminopyridines will exhibit similarly promising properties. These derivatives are likely to serve as important intermediates in drug development, materials science, and coordination chemistry, owing to the unique electronic and steric effects introduced by halogen substituents. Thus the study of intermolecular interactions of diaminopyridines with a set of additional substituents like halogen groups is essential for their potential drug development and crystal structure design.

In this contribution, we compare two selected amino-halogenopyridines with two related diamino-halogenopyridines in terms of their energetic profiles and their intermolecular interactions in the solid state.

2. Materials and Methods

The crystal structure analysis presented in this study was performed using methods based on the evaluation of pairwise intermolecular interaction energies within the investigated crystals [18,19,20]. For each independent molecular entity in the asymmetric unit (designated as M₀), its first coordination sphere was identified using a standard procedure implemented in the MERCURY program (version 4.2) [21]. Specifically, MERCURY enables the identification of molecules located in the immediate vicinity of M₀, based on geometrical criteria for standard intermolecular interactions. The details of this procedure have been previously thoroughly and clearly described [19,20]. Each resulting molecular cluster was divided into dimers consisting of M₀ and, in these cases, each neighboring molecule M_i from its coordination sphere. The atomic coordinates of all M₀–M_i dimers were extracted from the X-ray diffraction data, except for hydrogen atoms, whose positions were normalized to 1.089 Å for C–H bonds and 1.015 Å for N–H bonds. These values were derived from the geometry optimization of the isolated molecule. Normalization is necessary due to the well-known tendency of X-ray diffraction methods to underestimate X–H bond lengths [22].

The interaction energies within each M₀–M_i dimer were calculated using the B97-D3 density functional combined with the Def2-TZVP basis set [23,24,25,26,27]. The basis set superposition error (BSSE) was corrected using the counterpoise method [28]. The B97-D3 functional has been benchmarked as one of the most reliable dispersion-corrected functionals for modeling intermolecular interactions [29]. All calculations were performed using the ORCA 6.0 software package [30].

The analysis of pairwise interaction energies is based on the assumption that these interactions possess vector characteristics [19], with each calculated energy represented as originating from the geometric center of the reference molecule M₀ and oriented toward a neighboring molecule M_i. The vector length associated with each interaction was normalized to the strongest pairwise interaction energy in the crystal using the following equation:

L_i = (R_iE_i)/2E_str

Here, R_i denotes the distance between the geometric centers of the interacting molecules M₀ and M_i, E_i represents the interaction energy between the two molecules in each pair, and E_str is the energy of the strongest pairwise interaction identified within the crystal.

This normalization procedure ensures that the lengths of the resulting vectors are consistent regardless of the computational approach applied. This method allows the basic molecule to be represented by a set of energy vectors, facilitating the construction of an energy-vector diagram for each crystal structure based on symmetry operations.

3. Results and Discussion

Compounds 1–3 were sourced from the Cambridge Structural Database (CSD) [31] (

Table 1. Relevant crystal data for compounds 1–4.

№	Refcode	Space Group	Reference
1	AMCLPY12	P21/c	[33]
2	CAJXAN	P21/c	[11]
3	XEFMIH	P212121	[12]
4	CUFBAK	P212121	[32]

, Figure 1). In the case of multiple structures of the same compound, preference was given to those with better experimental data and more recent publication. The structural data of 4 originate from our lab and were published in advance as a structural report [32]. All structures were checked for systematical errors that may corrupt our quantum chemical investigation of the individual intermolecular interactions of each structure as well as the comparison of 1–4. As a first finding we can state that 3 and 4 are isotypical to each other. The shrinking of the unit cell from bromo-substituted 4 to the chloro-substituted 3 is 3.5% at almost the same measuring temperatures. This will affect some intermolecular distances, which need to be investigated in detail.

3.1. Analysis of the Molecular Structure

The functionality and directionality of an amino group attached to aromatic systems through intermolecular interactions as either a proton donor or acceptor are influenced by the extent of n–π conjugation between the nitrogen lone pair and the aromatic π-system. It is well established that the extent of this conjugation is significantly influenced by the polarizing environment [6,34,35]. Two key structural indicators of conjugation are the C–N bond length and the configuration of the N atom. At maximum conjugation, C–N bond length is minimized to have a partial double bonding, and the nitrogen atom adopts a strict planar configuration.

Investigation of the molecular geometry of compounds 1–4 showed that the C–NH₂ bond lengths vary between 1.355 Å and 1.408 Å, while the sum of bond angles around the nitrogen atoms ranges from 333° to 360° (

Table 2. Geometric parameters indicating the degree of conjugation between the amino group and the pyridine π-system in compounds 1–4.

Compound	C–N1, Å	C–N2, Å	∑N(1), Deg.	∑N(2), Deg.
1	1.360(7)		359
2	1.355(6)		360
3	1.385(4)	1.407(4)	348	342
4	1.380(5)	1.408(4)	346	333

). These variations indicate a broad spectrum of conjugation degrees between the NH₂ group and the pyridine ring, largely dependent on the substituent’s position. In the mono-amino-halogenopyridines 1 and 2, the amino group exhibits the highest degree of conjugation with the π-system of the aromatic ring. This is evidenced by the C_ar–N bond lengths (Table 2), which approximate the typical value for a planar nitrogen atom (1.355 Å) [36], as well as by the nearly planar geometry at the nitrogen center.

It is noteworthy that the two ortho-amino groups in compounds 3 and 4 are not equivalent (Table 2), likely due to their differing involvement in intermolecular interactions. As a result, in compounds 3 and 4, the NH₂ group is expected to be a hydrogen bond donor and acceptor, respectively. Comparable structural characteristics of amino groups have been previously reported in studies on unsubstituted aminopyridines [7].

3.2. Analysis of the Crystal Structures of Compounds 1–4: Focus on Geometrical Parameters of Intermolecular Interactions

In mono-amino-halogenopyridines (compounds 1 and 2), the NH₂ group and the heterocyclic nitrogen exhibits dual functionality, serving as a potent proton donor and acceptor. Therefore, the formation of N–H···N_pyr hydrogen bonds is expected in the crystal structures of these compounds. Additionally, the presence of a halogen atom suggests the potential for both halogen bonding (X-bonds [37,38]) and hydrogen bonding, where the halogen substituent may act as a proton acceptor.

Investigation of intermolecular interactions revealed that in the crystal of 1, a C–H···Cl hydrogen bond and a Cl···π interaction were observed (

Table 3. Geometric characteristics of intermolecular interactions in the crystals 1–2.

	Interaction	Symmetry Operations	H…A, Å	D–H…A, Deg.
1	N2–H···N1pyr	1 − x, 1 − y, 1 − z	2.20	179
	N2–H···N1mix	x, 0.5 − y, 0.5 + z	2.83	137
	C2–H···C5π	x, 0.5 − y, 0.5 + z	2.75	157
	C2–H···N1π	x, 0.5 − y, 0.5 + z	2.77	131
	C3–H···Cl	2 − x, 1 − y, 1 − z	2.98	167
	Cl···π	x, 1.5 − y, −0.5 + z	3.47
2	N2–H···N1pyr	2 − x, 1 − y, 2 − z	2.25	176
	C2–H···N1π	x, 1.5 − y, −0.5 + z	2.88	136
	C2–H···C1π	x, 1.5 − y, −0.5 + z	2.93	159
	Br···Br	1 − x, 0.5 + y, 1.5 − z	3.77

). In the crystal of compound 2, a Br···Br halogen bond was detected (Table 3).

Depending on the relative orientation of the interacting molecules, the N–H···N_pyr hydrogen bond can occur as a pure N–H···N interaction (when the C_ar–C_ar–N_pyr···H torsion angle exceeds 130°) or as a N–H···π interaction (when the angle is close to 90°) [39]. In many molecular crystals, hydrogen bonds of a mixed N–H···π/N–H···N type are observed when the C_ar–C_ar–N_pyr···H torsion angle falls within the 85–130° range, involving both the N atom’s lone pair and the π-system of the aromatic cycle.

Detailed analysis of the crystal structure of compound 1 revealed a strong N2–H···N1_pyr hydrogen bond (Table 3). The intermolecular N2–H···N1 interaction, characterized by a C–C–N···H’ torsion angle of 113°, can be defined as a mixed N–H···N/N–H···π H-bond (N2–H···N1_mix). Its parameters suggest it is significantly weaker than a pure classical N–H···N_pyr H-bond (Table 3). Furthermore, two weak C–H···π H-bonds were identified in the crystals of both compounds 1 and 2.

In the crystal of compound 1, centrosymmetric dimers are generated through the strongest N–H···N_pyr H-bonds (Figure 2). These dimers are stabilized not only by the mixed-type N–H···N hydrogen bond but also by C–H···π and C–H···Cl interactions. Double layers parallel to the bc plane are formed, which constitute the primary packing motif (Figure 2). It is noteworthy that this type of packing closely resembles that observed in 2-aminopyridine [7].

In the crystal of compound 2, the amino group forms a strong N2–H5···N_pyr hydrogen bond, similar to that observed between molecules of compound 1 (Figure 3). However, in this case, the resulting dimers are primarily stabilized by Br···Br halogen bonds, with additional contributions from C–H···π interactions. As a result, the same type of double-layered packing parallel to the bc plane is observed as in the crystal structure of compound 1 (Figure 3).

It is important to highlight that no stacking interactions are observed in mono-amino-halogenopyridines, despite the presence of the aromatic pyridine π-system and the higher conjugation degree of these molecules (Table 3). The same lack of stacking interactions has also been reported in the crystal structures of all isomers of diaminobenzenes and mono-aminopyridines [6,7].

Incorporating a second NH₂ group in compounds 3 and 4 enhances the quantity of strong proton donors as well as weak proton acceptors. Consequently, N–H···N_LP hydrogen bonds occur, with the amino group serving simultaneously as proton donor and acceptor, together with strong N–H···N_pyr hydrogen bonds.

Investigation of intermolecular interactions in crystals 3 and 4 showed that the interactions and their geometric characteristics are very similar. Each amino group creates two hydrogen bonds as a H donor. Only the more pyramidal N3(H₂) group functions as a H acceptor, forming a N2–H···N3_LP hydrogen bond (Table 2 and

Table 4. Geometric characteristics of intermolecular interactions in the crystals 3–4.

	Interaction	Symmetry Operations	H…A, Å	D–H…A, Deg.
3	N2–H···N1pyr	2 − x, −0.5 + y, 1.5 − z	2.19	167
	N2–H···N3LP	2 − x, −0.5 + y, 1.5-z	2.38	166
	N3–H···N1mix	−x, −0.5 + y, 1.5 − z	2.48	151
	C3–H···C3π	0.5 + x, 1.5 − y, 1 − z	2.89	153
	C5–H···Cl	1.5 − x, −y, 0.5 + z	2.87	169
	N3–H···Cl	0.5 + x, 1.5 − y, 1 − z	2.93	164
	C3–H···Cl	0.5 + x, 1.5 − y, 1 − z	3.01	148
	C2···C1, stacking	−1 + x, y, z	3.39
4	N2–H···N1pyr	−1 − x, 0.5 + y, 1.5 − z	2.31	167
	N2–H···N3LP	−1 − x, 0.5 + y, 1.5 − z	2.37	167
	N3–H···N1mix	−1.5 + x, 1.5 − y, 2 − z	2.46	153
	N3–H···C1π	−1.5 + x, 1.5 − y, 2 − z	2.81	130
	C5–H···Br	−0.5 − x, 2 − y, 0.5 + z	2.91	164
	N3–H···Br	−0.5 − x, 1 − y, 0.5 + z	3.09	166
	C2···C1, stacking	−1 + x, y, z	3.44

). Consequently, due to the N2–H···N1_pyr and N2–H···N3_LP hydrogen bonds the zig-zag chains oriented along the b crystallographic axis can be distinguished, similar to those observed in 2,6-diaminopyridine (Figure 4 and Figure 5) [7].

Concurrently, a weaker N3–H···N1 interaction occurs, where the pyridine nitrogen atom serves as the proton acceptor (Table 4). In this interaction, the C–C–N···H′ torsion angle is 107° in compound 3 and more or less identically 106° in compound 4, indicating the involvement of both the lone pair on the pyridine nitrogen atom and the pyridine π-system in proton acceptance. This type of interaction can be described as a hydrogen bond of mixed N–H···π/N–H···N character (N3–H···N1_mix), as observed in the crystal of 1 [39].

In addition, “head-to-head” type stacking interactions were identified (Figure 6), along with weaker C/N–H···Hal and C/N–H···π hydrogen bonds (Table 4). It should be noted that, from a general perspective, the crystal structures of compounds 3 and 4 are similar and can be classified as isotypical [40].

Summarizing the results of the crystal structure analysis from a geometrical perspective, the following conclusions can be drawn:

(a)

In mono-amino halogen pyridines 1 and 2, the amino group primarily participates in hydrogen bonding as a H donor;

(b)

Due to the presence of two amino groups, compounds 3 and 4 are simultaneously involved in hydrogen bonding interactions, acting as bifunctional proton donors and acceptors;

(c)

Stacking interactions are not observed in mono-amino-halogenopyridines;

(d)

Although geometric analysis is informative, it does not always allow for unambiguous interpretation of crystal packing motifs or the role of weak or non-specific interactions.

3.3. Energetic Perspective on the Crystal Structures of Compounds 1–4

As noted earlier, the use of geometric criteria alone does not provide a reliable basis for analyzing crystal packing in systems dominated by multiple weak interactions. An improved understanding of crystal packing can be obtained by calculating intermolecular interaction energies with ab initio methods [18,19,20]. The primary advantage of this method is its independence from the specific nature of the interactions, allowing it to comprehensively account for all types present, including hydrogen bonds, halogen bonds, dispersion forces, electrostatic interactions, polarization effects, and more. Importantly, this approach is applicable not only to single molecules as basic building units (BUs) of crystal packing but also to larger aggregates like dimers, trimers, or tetramers [20].

For each building unit (a molecule, dimer, or tetramer) located in the asymmetric unit of the unit cell, the first coordination sphere in all studied crystals contains 12–14 neighboring units.

Table 5. Summary of symmetry codes, interaction types, and interaction energies (E_int, kcal/mol) between the basic building unit and neighboring units whose interaction energies exceed 5% of the total, with corresponding relative contributions (ER, %) in the crystal structure of the compound 1.

Dimer	Symmetry Operation	Eint, kcal/mol	ER, %	Interaction
Building unit is a molecule
1-m1	1 − x, 1 − y, 1 − z	−12.02	24.3	N–H…Npyr 2.07 Å, 161°
1-m2	x, 1/2 − y, 1/2 + z	−6.44	13.0	N–H…Nmix 2.75 Å, 135°; C–H…π 2.68 Å, 156°; 2.72 Å, 130°
1-m3	x, 1/2 − y, −1/2 + z	−6.44	13.0	N–H…Nmix 2.75 Å, 135°; C–H…π 2.68 Å, 156°; 2.72 Å, 130°
1-m4	x, 1 + y, z	−3.66	7.4	non-specific
1-m5	x, −1 + y, z	−3.66	7.4	non-specific
1-m6	x, 3/2 − y, 1/2 + z	−3.58	7.3	C–H…π 2.83 Å, 157°
1-m7	x, 3/2 − y, −1/2 + z	−3.58	7.3	C–H…π 2.83 Å, 157°
1-m8	2 − x, 1 − y, 1 − z	−2.77	5.6	C–H…Cl 2.85 Å, 167°
Building unit is a dimer
1-d1	1 − x, 1/2 + y, 3/2 − z	−11.18	15.1	N–H…Nmix 2.75 Å, 135°; C–H…π 2.68 Å, 156°; 2.72 Å, 130°; 2.83 Å, 157°
1-d2	1 − x, −1/2 + y, 3/2 − z	−11.18	15.1	N–H…Nmix 2.75 Å, 135°; C–H…π 2.68 Å, 156°; 2.72 Å, 130°; 2.83 Å, 157°
1-d3	1 − x, −1/2 + y, 1/2 − z	−11.18	15.1	N–H…Nmix 2.75 Å, 135°; C–H…π 2.68 Å, 156°; 2.72 Å, 130°; 2.83 Å, 157°
1-d4	1 − x, 1/2 + y, 1/2 − z	−11.18	15.1	N–H…Nmix 2.75 Å, 135°; C–H…π 2.68 Å, 156°; 2.72 Å, 130°; 2.83 Å, 157°
1-d5	x, −1 + y, z	−8.60	11.6	non-specific
1-d6	x, 1 + y, z	−8.60	11.6	non-specific

,

Table 6. Summary of symmetry codes, interaction types, and interaction energies (E_int, kcal/mol) between the basic building unit and neighboring units whose interaction energies exceed 5% of the total, with corresponding relative contributions (ER, %) in the crystal structure of the compound 2.

Dimer	Symmetry Operation	Eint, kcal/mol	ER, %	Interaction
Building unit is a molecule
2-m1	2 − x, 1 − y, 2 − z	−12.55	24.7	N–H…Npyr 2.03 Å, 175°
2-m2	x, 3/2 − y, −1/2 + z	−5.97	11.8	C–H…π 2.79 Å, 158°; C–H…Nπ 2.77 Å, 134°
2-m3	x, 3/2 − y, 1/2 + z	−5.97	11.8	C–H…π 2.79 Å, 158°; C–H…Nπ 2.77 Å, 134°
2-m4	x, −1 + y, z	−3.88	7.7	non-specific
2-m5	x, 1 + y, z	−3.88	7.7	non-specific
2-m6	x, 1/2 − y, −1/2 + z	−3.86	7.6	C–H…π 2.88 Å, 136°
2-m7	x, 1/2 − y, 1/2 + z	−3.86	7.6	C–H…π 2.88 Å, 136°
2-m8	1 − x, 1 − y, 1 − z	−2.97	5.9	C–H…Br 3.10 Å, 173°
Building unit is a dimer
2-d1	2 − x, 1/2 + y, 5/2 − z	−10.94	14.4	C–H…π 2.79 Å, 158°; 2.88 Å, 136°; C–H…Nπ 2.77 Å, 134°;
2-d2	2 − x, −1/2 + y, 3/2 − z	−10.94	14.4	C–H…π 2.79 Å, 158°; 2.88 Å, 136°; C–H…Nπ 2.77 Å, 134°;
2-d3	2 − x, −1/2 + y, 5/2 − z	−10.94	14.4	C–H…π 2.79 Å, 158°; 2.88 Å, 136°; C–H…Nπ 2.77 Å, 134°;
2-d4	2 − x, 1/2 + y, 3/2 − z	−10.94	14.4	C–H…π 2.79 Å, 158°; 2.88 Å, 136°; C–H…Nπ 2.77 Å, 134°;
2-d5	x, 1 + y, z	−8.82	11.6	non-specific
2-d6	x, −1 + y, z	−8.82	11.6	non-specific

,

Table 7. Summary of symmetry codes, interaction types, and interaction energies (E_int, kcal/mol) between the basic building unit and neighboring units whose interaction energies exceed 5% of the total, with corresponding relative contributions (ER, %) in the crystal structure of the compound 3.

Dimer	Symmetry Operation	Eint, kcal/mol	ER, %	Interaction
3-m1	2 − x, −1/2 + y, 3/2 − z	−8.85	16.5	N–H…Npyr 2.08 Å, 166°; N–H…NLP 2.26 Å, 166°
3-m2	2 − x, 1/2 + y, 3/2 − z	−8.85	16.5	N–H…Npyr 2.08 Å, 166°; N–H…NLP 2.26 Å, 166°
3-m3	1 + x, y, z	−6.19	11.6	stacking, 3.45 Å
3-m4	−1 + x, y, z	−6.19	11.6	stacking, 3.45 Å
3-m5	1/2 + x, 3/2 − y, 1 − z	−5.69	10.6	N–H…Cl 2.79 Å, 163°; Cl…N 3.44 Å
3-m6	−1/2 + x, 3/2 − y, 1 − z	−5.69	10.6	N–H…Cl 2.79 Å, 163°; Cl…N 3.44 Å
3-m7	1 − x, −1/2 + y, 3/2 − z	−4.18	7.8	N–H…Npyr 2.35 Å, 149°
3-m8	1 − x, 1/2 + y, 3/2 − z	−4.18	7.8	N–H…Npyr 2.35 Å, 149°

and

Table 8. Summary of symmetry codes, interaction types, and interaction energies (E_int, kcal/mol) between the basic building unit and neighboring units whose interaction energies exceed 5% of the total, with corresponding relative contributions (ER, %) in the crystal structure of the compound 4.

Dimer	Symmetry Operation	Eint, kcal/mol	ER, %	Interaction
4-m1	−x, 1/2 + y, 3/2 − z	−8.94	16.1	N–H…Npyr 2.08 Å, 166°; N–H…NLP 2.29 Å, 167°
4-m2	−x, −1/2 + y, 3/2 − z	−8.94	16.1	N–H…Npyr 2.08 Å, 166°; N–H…NLP 2.29 Å, 167°
4-m3	−1 + x, y, z	−6.79	12.2	stacking, 3.49 Å
4-m4	1 + x, y, z	−6.79	12.2	stacking, 3.49 Å
4-m5	1/2 + x, 1/2 − y, 1 − z	−5.70	10.3	N–H…Br 2.89 Å, 165°; Br…N 3.47 Å
4-m6	−1/2 + x, 1/2 − y, 1 − z	−5.70	10.3	N–H…Br 2.89 Å, 165°; Br…N 3.47 Å
4-m7	1 − x, 1/2 + y, 3/2 − z	−4.38	7.9	N–H…Npyr 2.34 Å, 152°
4-m8	1 − x, −1/2 + y, 3/2 − z	−4.38	7.9	N–H…Npyr 2.34 Å, 152°

summarize data for dimers whose interaction energies exceed 5% of the total interaction energy between the basic molecule and its first coordination sphere.

In the structure of 1, the total interaction energy between the basic molecule and its 14 neighboring molecules is −42.1 kcal/mol. Pairwise interaction analysis reveals one dominant interaction (Table 5, dimer 1-m1) with an energy of −12.02 kcal/mol that is nearly twice as high as the interaction energy with any other neighbor. Consequently, this dimer, stabilized by a N–H···N_pyr hydrogen bond, can be considered a complex dimeric building unit in structure 1 (Figure 7a).

Further analysis of the first coordination sphere of this dimer shows that it is surrounded by 14 neighboring dimers, with a total interaction energy of −74.2 kcal/mol. The strongest interactions are formed with four of these dimers (Table 5), all of which lie on a common plane. As a result, a layer of dimers can be identified as the primary basic structural motif (BSM) in the crystal of 1 (Figure 7b,c). The interaction energy of the dimeric BU within this layer is −61.9 kcal/mol, with interactions involving mixed N–H···N/N–H···π hydrogen bonds (N–H···N_mix), C–H···π contacts, and non-specific interactions. Weaker interlayer interactions (−12.2 kcal/mol) are mediated by C–H···Cl hydrogen bonds and Cl···Cl halogen bonds. A similar type of crystal packing was previously observed in the structures of 2-aminopyridine and 1,2-diaminobenzene [6,7].

The first coordination sphere of the basic molecule in structure 2 also includes 14 neighbors, with a slightly higher total interaction energy (−50.7 kcal/mol). Similar to structure 1, one strongest pairwise interaction is observed (Table 6, dimer 1-m1), identifying this dimer as the dimeric BU of the structure (Figure 8). The dimer is surrounded by 14 other dimers (total interaction energy −76.1 kcal/mol) and forms four dominant interactions within a layer (Figure 8), resulting in a layer of dimers as the primary BSM. The interaction energy within this layer is −61.4 kcal/mol. Dimers are connected via C–H···π hydrogen bonds and non-specific interactions. The weaker interlayer energy (−14.7 kcal/mol) is due to C–H···Br hydrogen bonds and Br···Br halogen bonds.

In structure 3, the basic molecule is surrounded by 12 neighboring molecules, with a total interaction energy of −53.5 kcal/mol. The pairwise analysis reveals two strongest interactions (dimers 3-m1 and 3-m2), each with an energy of −8.85 kcal/mol, located in opposite directions (Table 7). These dimers form a zig-zag column, which serves as the primary BSM (Figure 9). The total interaction energy of the molecule within this column is −17.7 kcal/mol.

The anisotropic nature of the interactions between primary BSMs allows for the separation of layers of columns, defining the secondary BSM (BSM2) in structure 3. Within these layers, neighboring columns are connected by stacking interactions. The calculated interaction energy of the basic molecule in the layer amounts to −38.4 kcal/mol. This interaction energy is over three times greater than that observed between adjacent layers (−11.4 kcal/mol). The interlayer contacts involve weaker N–H···Cl hydrogen bonds and Cl···N interactions. Hence, structure 3 exhibits two levels of supramolecular organization (Figure 9). Notably, the N–H···N_LP hydrogen bond, in which the amino group acts as a proton acceptor, plays a key role in crystal formation alongside the classical N–H···N_pyr hydrogen bond.

In structure 4, the first coordination sphere also includes 12 neighboring molecules, with a total interaction energy of −55.5 kcal/mol. Similar to structure 3, two strongest interactions are observed (Table 8), forming a zig-zag column as the primary BSM (Figure 10). The bond angle defined by the geometric centers of the basic building unit and adjacent molecules measures approximately 90.9° in structure 3 and 91.1° in structure 4. Molecules within the column are linked by N–H…N_pyr and N–H…N_LP hydrogen bonds. The total interaction energy within the column is −17.9 kcal/mol.

Likewise, a layer of columns can be identified as the secondary BSM. The interaction energy of the basic molecule with neighbors within this layer is −40.2 kcal/mol, while the interlayer energy is −11.4 kcal/mol. Thus, structure 4 also exhibits columnar-layered packing and can be characterized as isotypical with structure 3.

4. Conclusions

We have analyzed the molecular and crystal structures of mono- and diamino-substituted halogenated pyridines (chloro- and bromo-derivatives). The molecular and crystal structure analysis from a geometric perspective reveals that amino groups participate in hydrogen bonding, acting as bifunctional proton donors and acceptors only in the diamino-substituted compounds. Notably, no stacking interactions were observed in the mono-amino-substituted halogen pyridines.

Energetic analysis of crystal packing demonstrates that the nature of the building unit, basic structural motifs, and overall packing organization differ significantly among crystals 1–4. In the crystal structures of 2-amino-5-chloropyridines (1) and 2-amino-5-bromopyridines (2), layers were identified as the primary structural motif, with C–H···π hydrogen bonds playing a key role in crystal stabilization.

In contrast, the diamino-substituted chloro- and bromopyridines are isotypical, exhibit two levels of organization, and can be classified as columnar-layered. In these structures, N–H···N_pyr and N–H···N_LP hydrogen bonds, in combination with π–π stacking interactions, are the dominant forces governing crystal formation. Meanwhile, weaker C–H···Hal hydrogen bonds, halogen bonds, and other non-specific interactions play a minor role, mainly in connecting neighboring layers.