Structural and Energetic Analysis of Molecular Assemblies in a Series

Article pubs.acs.org/crystal

Structural and Energetic Analysis of Molecular Assemblies in a Series of Nicotinamide and Pyrazinamide Cocrystals with Dihydroxybenzoic Acids Published as part of a Crystal Growth and Design virtual special issue Honoring Prof. William Jones and His Contributions to Organic Solid-State Chemistry Katarzyna N. Jarzembska,*,†,# Anna A. Hoser,‡,# Sunil Varughese,§,∥ Radosław Kamiński,† Maura Malinska,‡ Marcin Stachowicz,‡ Venkatesvara R. Pedireddi,⊥ and Krzysztof Woźniak*,‡ Department of Chemistry and ‡Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Ż wirki i Wigury 101, 02-089 Warsaw, Poland § Chemical Science and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Trivandrum 695 019, Kerala, India ∥ Academy of Scientific and Innovative Research, Delhi-Mathura Road, New Delhi 110 025, India ⊥ Indian Institute of Technology, Bhubaneswar 751 013, India †

S Supporting Information *

ABSTRACT: Four new cocrystals of pharmaceutically active N-donor compounds, pyrazinamide (P) and nicotinamide (N), with a series of dihydroxybenzoic acids, i.e., 2,3dihydroxybenzoic acid (23DHB), 2,4-dihydroxybenzoic acid (24DHB), and 2,6-dihydroxybenzoic acid (26DHB), were synthesized and structurally evaluated in order to study basic recognition patterns and crystal lattice energetic features. The literature-reported structures of this kind, i.e., N:24DHB, N:25DHB and N:26DHB (the last two were crystallized and remeasured by us at 100 K) and P:25DHB, completed the series. The analysis of interaction networks in the examined cocrystals reflects the relative affinity of the COOH and OH groups toward N-donor compounds. A major factor that governs the primary synthon formation is the basic character of the proton acceptors in the heterocyclic compounds. In a crystal lattice, the more rigid pyrazinamide tends to form its primary structural motifs, and hence is less influenced by the molecular surrounding than nicotinamide. Consequently, crystal lattice stabilization energy values for the cocrystals of nicotinamide are more advantageous, whereas the patterns created by pyrazinamide are more predictable. Nicotinamide cocrystals are also characterized by crystal lattices being more energetically uniform in all directions than the pyrazinamide equivalents. Importantly, cocrystal cohesive energies are more favorable than that of the respective single component crystal structures, which supports the cocrystal formation when both coformers are dissolved and mixed together. Although classical hydrogen bonds are majorly responsible for synthon formation, weak dispersive forces cannot be neglected either as far as the structure stabilization is concerned.

1. INTRODUCTION

the other hand, more directional than other intermolecular interactions. Such properties of hydrogen bonds allow for finetuning and optimizing the self-assembly phenomena.15 There are several methods of analysis and description of mutual orientation of the crystal structure components in a crystal lattice in terms of recognition patterns.1,10,16−18 For instance, structural motifs and the graph set notation describe features of existing crystal structures, whereas the synthon concept indicates various ways in which complementary molecules may approach one another. A thorough understanding of supramolecular synthons, their preferred geo-

Crystal engineering deals with the design and synthesis of solid state assemblies with desired chemical and physical properties.1−7 It has been recently shown that physicochemical properties of a given compound in the solid state can be tuned by its cocrystallization with an appropriately selected coformer. In order to find the most suitable coformers, it is indispensable to understand how a given molecule may interact with the compound of interest and what kind of three-dimensional (3D) network is expected. Therefore, it is of high importance to study the nature and strength of intermolecular interactions and their directing role in the self-assembly processes.8−13 Considering the organic assemblies, hydrogen bonds constitute a crucial class of noncovalent interactions4,10,14 being weaker and more flexible than conventional covalent bonds, and, on © 2017 American Chemical Society

Received: June 20, 2017 Revised: July 27, 2017 Published: August 1, 2017 4918

DOI: 10.1021/acs.cgd.7b00868 Cryst. Growth Des. 2017, 17, 4918−4931

Crystal Growth & Design

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synthesized and remeasured by us at 100 K), two polymorphs of N:24DHB57 (REFCODEs: DINRUP & DINRUP01; RT data; here denoted as N:24DHB-I and N:24DHB-II), and the respective representative literature-available single-component systems (for full information see Table 4). In the case of P and N which appear as various polymorphic forms, we have selected the most commonly crystallized polymorphs for comparison purposes. The analyzed crystal structures were characterized in terms of crystal packing and structural motifs. For all the investigated cocrystals cohesive energy calculations in the CRYSTAL58,59 and PIXEL60,61 packages were performed, while the interaction energies were additionally derived for selected supramolecular motifs. Moreover, as apart from the strength of intermolecular interactions, their directionality is crucial in determining the crystal network overall stability and its physicochemical properties, energy frameworks62 were also calculated and examined.

metries, competitive hydrogen bonds, interaction strength, etc. should result in rational design and noncovalent synthesis of novel assemblies.19−24 Such knowledge provides also some greater insight into various biological recognition occurrences, such as ligand-protein binding.25 A systematic quantitative evaluation of binding strength and nature of synthons provides an additional dimension to our understanding of the intermolecular interactions and their stabilizing role in the structure formation. In the current study, we continue our structural and energetic investigations of hydrogen bonds leading to hydroxyl-group···pyridine-fragment O−H···N heterosynthons in the presence of competitive hydrogen-bonding functional groups, extending our previous analysis of dihydroxybenzoic acids (DHBs) cocrystals with bipyridyls26 by those with nicotinamide (N) and pyrazinamide (P).27−29 Dihydroxybenzoic acids constitute a very interesting group of compounds in terms of crystal engineering, as they can exist as six positional isomers and form complex hydrogen bond networks. 30 Among others, DHBs can create various interaction patterns with N-donor compounds due to the variably arranged hydroxyl and carboxylic functionalities with a competent ability to form robust hydrogen bonds.31−36 In turn, pyrazinamide is a compound of significant pharmaceutical interest, being a frontline antituberculosis drug.37−42 Up to now, 30 different organic pyrazinamide-containing cocrystal structures and one salt-like complex structure are known. Nevertheless, most of the reports concerning pyrazinamide are related to its pharmaceutical properties,37−42 or encompass its polymorphic behavior.43−47 On the other hand, nicotinamide, being a GRAS (generally recognized as safe) compound, has been more extensively studied by crystal engineering methods,48−51 which resulted in a vast number of cocrystal structures (101 different cocrystals and 20 different salt-like structures) available in the Cambridge Structural Database (CSD).52 Both P and N have been previously thoroughly analyzed by us in terms of charge density distribution.53 In this contribution we present four new cocrystal structures of DHBs with nicotinamide or pyrazinamide (Scheme 1), i.e., N:23DHB, P:23DHB, P:24DHB, and P:26DHB. The series was supplemented with the analogous cocrystals already present in the CSD, namely, P:25DHB54 (REFCODE: XAQQOW), N:25DHB55 and N:26DHB56 (REFCODEs: PEKRUU and LAGTOF & LAGTOF01, respectively; both

2. EXPERIMENTAL SECTION 2.1. Materials and Crystallization. All substrates were purchased from commercial sources. Cocrystals were obtained from equimolar substrate methanol solution via a standard solvent evaporation method. 2.2. X-ray Data Collection and Refinement. Single-crystal X-ray measurements of all compounds were carried out on a classical diffractometer (Rigaku Oxford Diffraction, formerly KUMA Diffraction), equipped with a CCD detector and low-temperature open-flow device to keep the samples at the temperature of 100 K. Data collection strategies determination and optimization, unit cell determination, raw diffraction image integration, and data scaling were all performed using the appropriate algorithms implemented in the diffractometer software.63 All structures were solved using direct methods as implemented in the SHELXS program,64 and refined with the SHELXL program64 within the independent atom model (IAM) approximation. CIF files for each refinement can be retrieved from the CSD (for deposition numbers see CCDC 1554966−1554971). 2.3. Hirshfeld Surface Analysis. This method allows for fast identification of the shortest possible intermolecular contacts and, subsequently, for their quantification. Hirshfeld surfaces (HSs) and fingerprint plots (FPs) for all the studied systems, i.e., for the nicotinamide molecule in N:23DHB, N:24DHB-I, N:24DHB-II, N:25DHB, and N:26DHB, and for the pyrazinamide molecule in P:23DHB, P:24DHB, P:25DHB, P:26DHB, were generated using the CRYSTALEXPLORER program,65 and are available in the Supporting Information. 2.4. Computational Studies. The geometry of all crystal structures was optimized at the DFT(B3LYP)/6-31G** level of theory66−69 in the CRYSTAL program (CRYSTAL09 version)58,59 prior to further computational analyses. During the optimization procedure cell parameters were kept fixed while the atom positions varied. Crystal cohesive energies for the studied crystal systems were calculated at the same level of theory. The results were corrected for dispersion70−72 and the basis set superposition error (BSSE).73 Ghost atoms used for the BSSE estimation were selected up to 5 Å distance from the considered molecule in the crystal lattice. The evaluation of Coulomb and exchange series was controlled by five thresholds, set to the values of 10−7, 10−7, 10−7, 10−7, and 10−25. The general methodology was analogous to that described in our previous papers.74−76 The intermolecular interaction energies evaluation was conducted using the GAUSSIAN package77 (GAUSSIAN09 version). In this case the DFT(B3LYP)/aug-cc-pVDZ66−68,78,79 method was employed with the Grimme empirical dispersion correction71,72 modified by the Becke-Johnson damping function,80,81 and correction for BSSE.73,82 The GAUSSIAN package was also employed to calculate the nicotinamide and pyrazinamide amide fragment rotation barrier. Atomic partial charges were determined using the Merz−Kollman−

Scheme 1. Components of the Analyzed Cocrystals: Nicotinamide (N), Pyrazinamide (P), 2,3-Dihydroxybenzoic Acid (23DHB), 2,4-Dihydroxybenzoic Acid (24DHB), 2,5Dihydroxybenzoic Acid (25DHB), and 2,6Dihydroxybenzoic Acid (26DHB)

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Figure 1. Selected hetero- (I, I′, IST, II, II′, III, III′, IV) and homosynthons (V, VI, VII, VIII), which appear in the available cocrystals of nicotinamide and pyrazinamide with aromatic carboxylic acids (either from the CSD-derived, or our newly synthesized structures; (N) atom means the dimer is present in cocrystals of both nicotinamide and pyrazinamide). Please note that some dimers may in fact exhibit various conformations and/or be supported by a variety of secondary interactions in the solid state and here are presented in an idealized way. Singh fit to electrostatic potentials.83,84 Geometry optimizations were performed at each rotational step (every 2°) keeping the restricted O− C−C−C torsion angle value (τO−C−C−C). All input files for either CRYSTAL or GAUSSIAN programs were prepared using the CLUSTERGEN program.85 Additionally, for comparison purposes and estimation of different total energy components, PIXEL60,61 energy calculations were performed. The optimized crystal structures were used to calculate the molecular electron density by standard quantum chemical methods with the GAUSSIAN program (GAUSSIAN98 version) at the MP2/631G** level of theory.69,86 The electron density model of the molecule was then analyzed using the PIXEL program package,60,61 which allows for calculation of dimer and cohesive energies. A cluster of molecules of radius 18 Å was used for lattice energy evaluation. PIXEL provides crystal cohesive energy and also its breakdown into electrostatic, polarization, dispersion, and repulsion components. The CRYSTALEXPLORER program65 (CRYSTALEXPLORER17 version) was also used to evaluate interaction energies for selected dimers present in the studied cocrystals. Similarly as in PIXEL, the total energy of a given dimer constitutes the sum of electrostatic, polarization, dispersion, and exchange-repulsion components. The molecular electron density was calculated at the DFT(B3LYP)/631G** level of theory using the above-described CRYSTAL-optimized molecular geometries. The dimer interaction energies were further utilized to generate the so-called energy frameworks.62

different nicotinamide:carboxylic acid cocrystals available in the CSD follow Etter’s empirical rule16 that intermolecular hydrogen bonds are formed between the best proton donors and acceptors remaining after formation of intramolecular hydrogen bonds. Thus, in the reported complexes the most acidic proton from the carboxylic fragment, which is the best hydrogen bonding donor, should interact with the best hydrogen bonding acceptor, i.e., the basic lone pair of the pyridine nitrogen atom. Indeed, such an interaction (synthon I; see Figure 1 for all synthon schemes) is present in a vast majority of the nicotinamide cocrystals, i.e., 57 which constitutes 80% of the analyzed population. In certain cases, characterized by a sufficient difference of the relative acidity and basicity of the two components, formation of synthon I can even induce a proton transfer between carboxylic and pyridine centers. In turn, the most prevailing motif involving the N amide group is synthon V. In the case of pyrazinamide, the literature-available set of cocrystals is much more limited than that for nicotinamide. Up to now, 18 different pyrazinamide structures with carboxylic acids have been reported. As the P molecule contains an additional nitrogen atom in the aromatic ring when compared to N, namely, N1 at the closest vicinity to the amide fragment (Figure 2), it can be noticed that P is more robust and conformationally predictable. This is reflected in the usually lower number of various synthons encountered in its known cocrystals. However, at the same time an additional synthon VII can be found. Concerning the reported cocrystals with carboxylic acids, in six of them the mixed P:carboxylic-acid

3. RESULTS AND DISCUSSION 3.1. General Remarks. As nicotinamide is a GRAS substance and a stated coformer, a few database analyses of its cocrystals with carboxylic acids have already been reported.49,50 Hence, here we just recall the robust synthons formed between the N molecule and carboxylic acids. The 71 4920



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more visible in the case of P due to the formation of the intramolecular hydrogen bond in the anti conformation). In the case of nicotinamide, the pyridine N atom (N1, Figure 2a,b) is the best nucleophilic center and thus should preferably interact with the −COOH group of DHBs leading to synthon I. In turn, the carboxamide fragment, being both a proton donor and acceptor, should form hydrogen bonds with the −OH groups of DHBs. The assignment of the pyridine nitrogen of N as the most nucleophilic site is supported by its most negative charge, ca. − 0.70 e, followed by the amide carbonyl oxygen (−0.53 e). In the case of P, N1 influences the molecular charge distribution, and, consequently, pyridine nitrogen N2 has reduced nucleophilic character (Figure 2d). Thus, different synthons involving pyrimidine N atoms and the amide group are favored. The O atom from the amide group constitutes the best proton acceptor and, hence, should bind with the carboxyl group, the most acidic site, leading to the synthon II. Since the N2 is more accessible and constitutes a better nucleophile than N1, it is preferably involved in intermolecular hydrogen bonds, binding with the −OH groups of DHBs (synthon I′). N1 may participate in weaker intermolecular interactions, due to its close vicinity to the amide fragment with which N1 preferably forms intramolecular hydrogen bond in accordance with Etter’s rules. A visible change in charge density is also observed at the carbon and hydrogen atoms in the aromatic ring fragment. However, these protons are significantly less acidic than those from the amide moiety, and such differences will only affect the formation of C−H···π interactions and other secondary contacts. Another important issue, when comparing P and N molecules, is the rotational liability of the amide substituent; thus the conformational energy analysis concerning the O−C− C−C torsion angle has been performed. In the case of nicotinamide, there are two main energy minima, i.e., a global minimum around ±162° (syn amide group conformation, Figure 2) and a local minimum at about ±22° (anti amide group conformation, Figure 2), as the energy curve has a mirror plane at 0° (these results are in agreement with similar calculations for nicotinamide performed earlier by Bathori et al.49 and Lemmerer et al.).50 The energy difference between the two orientations of the amide group amounts to only about 4 kJ·mol−1 in favor of the syn arrangement, whereas the energy barrier between the syn and anti conformations reaches 16 kJ· mol−1. Therefore, the amide group in N can exhibit either syn or anti orientation according to the N-pyridine atom. This is well reflected in the conformation histogram based on the nicotinamide containing structures in the CSD (Figure 3a). There are two well-defined conformational peaks corresponding to the two energy minima, among which the more stable syn conformation is indeed more populated. In turn, from the respective histogram and the energy curve (Figure 3b) it is evident that the P molecule is conformationally more restricted. The presence of N1 in the aromatic ring hampers the rotation of the amide fragment. N1 interacts with the H atom from the amino group, forming a weak intramolecular hydrogen bond, which stabilizes the anti conformation of the amide moiety according to the N2 atom. The anti conformation is strongly favored (over 30 kJ·mol−1 difference between the global (0°, anti) and local (±138°, syn) energy minima). Indeed, the amide group in all the measured (Table 1) and literature-available structures is characterized by the O−C−C−C torsion angle around 0°. When slightly rotated, it is just due to the crystal packing effects.

Figure 2. Partial charges fitted to electrostatic potential (DFT(B3LYP)/aug-cc-pVDZ level of theory) for both nicotinamide (a, b) and pyrazinamide (c, d) in the energy minima corresponding to their syn (a, c) and anti (b, d) conformations. Please note that for (a), (b), and (c) figures the amide-group-to-aromatic-ring torsion angle deviates significantly from 180°, whereas in (d) the molecule is planar (due to the presence of intramolecular hydrogen bond) (see also Figure 3).

synthon II is formed. Otherwise, synthon V engages the amide group, whereas the carboxylic moieties may either interact with one another, or with the N2 atom. Considering the character of nicotinamide and pyrazinamide molecules and that of dihydroxybenzoic acids, it is apparent that the mutual recognition of such crystal components is based mainly on the interaction of −OH and −COOH with the heteroatoms of N-donor compounds. In this respect, the chemical nature of heteroatoms in N-donor molecules is crucial to understand preferences in synthon formation in the studied series of cocrystals, and to explain the trends observed when analyzing the CSD entries. As already mentioned before, an obvious difference between pyrazinamide and nicotinamide species is the presence of additional nitrogen in the aromatic ring of P. This feature significantly changes the conformational preferences of the amide substituent and the mutual basicity of the pyrimidine nitrogen atom and carbonyl group in P when compared to N. The density functional theory (DFT) calculation of atomic partial charges fitted to the electrostatic potential (Figure 2) confirms that structural differences between these two moieties have a significant effect on the charge density distribution on the heteroatoms. The same conclusion can be drawn when comparing the QTAIM-derived charges from our previous work.53 Furthermore, computations show a minor, though noticeable, effect of the amide group conformation on the charge distribution (which is naturally 4921



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Table 1. O−C−C−C Torsion Angle (τO−C−C−C) Values Exhibited by Nicotinamide and Pyrazinamide in the Analyzed Experimental and the Literature-Available Supplementary Crystal Structuresa τO−C−C−C/° crystal structure

X-ray geom

optimized geom

N:23DHB N:24DHB-Ib,c N:24DHB-Ib,d N:24DHB-IIb,e N:25DHB N:25DHBRTb,f N:26DHBg P:23DHB P:24DHB P:25DHB P:26DHB Nαb,h Pαb,i Pβb,j

+147.2(2) (syn) +10.6 (anti) k +179.3 (syn) +159.2(1) (syn) −158.5 (syn) −11.5(2) (anti) +7.9(2) (anti) −3.9(3) (anti) +0.3(3) (anti) +11.0(2) (anti) −157.5 (syn) −4.7 (anti) −2.3 (anti)

+146.25 (syn) +16.22 (anti) +18.54 (anti) +170.04 (syn) +157.91 (syn) −157.36 (syn) −12.37 (anti) +9.35 (anti) −4.39 (anti) +1.08 (anti) +13.02 (anti) −156.81 (syn) −7.12 (anti) −3.53 (anti)

a

Every value is followed by the description of the molecule conformation; N/Pα/β means either α or β phase for nicotinamide or pyrazinamide. bStructure retrieved from CSD and optimized with the CRYSTAL program (additionally underlined). c The first polymorph of the N:24DHB structure (REFCODE: DINRUP) with the OH group disorder removed (the ortho-OH group is farther away from the protonated oxygen from the carboxylic group). dSame as point (b) (REFCODE: DINRUP) but with the OH group located at the second ortho-position. eThe second polymorph of the N:24DHB cocrystal (REFCODE: DINRUP01). fSame as N:25DHB but measured at room temperature (REFCODE: PEKRUU). Note change in sign due to the different enantiomer. gIonic structure. hREFCODE: NICOAM01. iREFCODE: PYRZIN15. jREFCODE: PYRZIN18. k Same experimental structure as in point (b) − only optimized structures are different.

Figure 3. Graphs for nicotinamide (a) and pyrazinamide (b) showing plots of relative molecular energy (Erel) vs the O−C−C−C torsion angle (τ), and the CSD-derived histograms for the same angle. Next to the τ-constrained optimization energy minima the respective idealizedgeometry schemes are presented.

as a ring motif R22(9), is particularly distinctive and formed by N solely with the 23DHB acid thanks to its neighboring hydroxyl groups. Because of multiple hydrogen bond donor and acceptor centers in the coformers, hydrogen bonding interactions in the studied cocrystals extend the described synthons into 1−3D architectures stabilized further by π···π secondary interactions and other dispersive contacts. Hence, in the case of N:23DHB one can observe molecular planes formed by hydrogen-bondconnected ladder-like motifs (Figure 4a), which then interact one with another by C−H···π contacts. In turn, hydrogenbonded chain motifs are present in both literature-reported polymorphs of N:24DHB. In the case of the N:24DHB-II form (REFCODE: DINRUP01) flat chains are created by synthons II (R22(8) − carboxyl-amide group interaction) and I′ (interaction of the para-hydroxyl group with the N pyridine atom). The adjacent chains are connected via the N−H···O hydrogen bonds forming molecular tapes (Figure 4c). Various C−H···O contacts link such tapes into molecular layers, while π···π stacking interactions stabilize further such a layered architecture. In N:24DHB-I chain motifs resemble more closely these encountered in the remaining nicotinamide cocrystal structures; i.e., synthon I is the major dimer, whereas the amide group is involved in three heteromeric interactions via hydrogen bonding (Figure 4b). The chains are interconnected one with another forming an efficient 3D hydrogenbonded network. Similar chain motifs and 3D hydrogen-

3.2. Cocrystals of Nicotinamide with Dihydroxybenzoic Acids. The aforesaid features of the molecular charge density distribution and, thus, properties of nicotinamide and pyrazinamide are reflected in the favorable structural motifs present in their respective cocrystals. As the nitrogen atom from the heteroaromatic ring in N is more negative than the corresponding one in P (Figure 2), nicotinamide forms preferably synthon I with DHBs rather than synthon II, which is predominant in the P equivalents. In the case of synthon I the carboxylic group is involved in the relatively strong O−H···N hydrogen bond with the pyridine N atom. The DFT-estimated interaction energy characterizing such a synthon varies between −60 and −70 kJ·mol−1 (Table 2). The only nicotinamide cocrystal structure, in which synthon I is not observed, is the N:24DHB-II polymorph. Instead, synthons I′ and II are encountered in N:24DHB-II, among which the latter one is characterized by the most stabilizing interaction energy (−86.7 kJ·mol−1) in the N series. The flexibility of the amide group from N and the fact that it is rarely involved in synthon II facilitate creation of a greater variety and number of hydrogen bonds when compared to P. Consequently, this function assists formation of heterosynthons II′, III, III′, IV, and homosynthon VI. Among them, the wellstabilized synthon II′ (−43.5 kJ·mol−1), which can be described 4922



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Interestingly, carbonyl oxygen atom from the amide function is not engaged in any significant interactions and mediates only some weak C−H···O contact. Synthon I and two types of synthon III′ expand the hydrogen-bonded network into flat molecular layers, interacting further via π···π stacking, stabilizing the 3D crystal architecture. 3.3. Cocrystals of Pyrazinamide with Dihydroxybenzoic Acids. As mentioned before, a general observation which can be made for pyrazinamide cocrystals with dihydroxybenzoic acids is that in all the studied cases synthon II is preferably formed. It involves the carboxylic group from the acid molecule and the amide fragment from P. Such created molecular complexes are stabilized via two hydrogen bonds leading to the R 22 (8) ring motif according to Etter’s notation. The corresponding interaction energy varies from −81.8 kJ·mol−1 for P:24DHB up to −96.2 kJ·mol−1 for P:26DHB (Table 2). Because of the two relatively strong hydrogen bonds this synthon is the strongest-stabilized one among the studied cocrystals. The other synthon present in all the pyrazinamide cocrystals is I′, which also constitutes the second motif in the P:acid set in terms of interaction energy. In the case of P:24DHB and P:25DHB the derived interaction energy exceeds −40.0 kJ·mol−1, whereas it is weaker in the P:23DHB and P:26DHB cocrystals (Table 2) due to the close vicinity of an additional oxygen atom to the interacting OH moiety. In the case of 23 and 24DHBs, the hydroxyl group in positions 3 or 4 facilitates chain motif formation (Figure 5a,b). Furthermore, in P:24DHB the neighboring chains are interconnected via hydrogen bond interactions between inversion-center-related pyrazinamide molecules (synthon VII, see Figures 1 and 5b, dimer interaction energy equals −23.6 kJ· mol−1). This leads to a more energetically efficient packing than it is in the case of P:23DHB, in which only more distant weaker interactions are observed. In the P:25DHB and P:26DHB cocrystals the DHB hydroxyl groups at positions 5 and 6 stimulate ring motif rather than chain pattern formation (Figure 5c,d). Additionally, in P:25DHB the oxygen atom from the hydroxyl group, besides being a proton donor in hydrogen bonding with N2 from pyrazinamide, acts as an acceptor for the proton from the amide group of pyrazinamide (synthon III′, dimer interaction energy equals −17.6 kJ·mol−1). Ring motifs form further undulated hydrogen-bonded layers interacting one with another by dispersive interactions. In turn, in P:26DHB such molecular rings lead to infinite tapes (Figure 5d). Such tapes interact via π···π stacking and some other secondary contacts. In general, no 3D hydrogen-bonded network is observed in the P cocrystal series. It is also worth mentioning that in P:26DHB the heterosynthon III′ is weaker-stabilized (dimer interaction energy equals −12.1 kJ·mol−1) than the P··· P homosynthon present in this crystal structure (the respective dimer interaction energy amounts to −16.4 kJ·mol−1). 3.4. Molecular Motifs. The interaction energies of the above-mentioned dimeric motifs were calculated using three basic approaches. The classical DFT (performed with the GAUSSIAN program) and PIXEL methods were supplemented with a new fast and efficient approach recently proposed by Turner et al.62 Figure 6 shows comparison of the GAUSSIAN, PIXEL, and CRYSTALEXPLORER results obtained for the hydrogen-bonded complexes in the analyzed series of cocrystals (for computational details see the Experimental Section). It occurs that all used computational methods provide the same energy trends ranking dimers in a given cocrystal structure.

Table 2. Interaction Energies for Selected Hydrogen-Bonded Synthons Present in the Analyzed Cocrystalsa cocrystal N:23DHB

N:24DHB-Ic,d

N:24DHB-Ic,e

N:24DHB-IIc,f

N:25DHB

N:25DHBRTc,g

N:26DHBh

P:23DHB P:24DHB

P:25DHB

P:26DHB

dimer motif

b EGAUSS /kJ·mol−1 int

I II′ VI I III III′ IV I III III′ IV I′ II III′ I III′i III′i IV I III′i III′i IV IST III′i III′i I′ II I′ II VII I′ II III′ I′ II III′

−67.9 −43.5 −42.0 −58.8 −20.3 −14.9 −49.3 −64.9 −25.2 −14.6 −51.1 −50.1 −86.7 −23.2 −66.7 −19.4 −17.0 −44.0 −66.3 −19.5 −17.5 −44.0 −410.7 −292.3 −223.8 −31.7 −82.1 −43.7 −81.8 −23.6 −41.8 −84.4 −17.6 −21.0 −96.2 −12.1

a GAUSS Eint b

are the energies computed with the GAUSSIAN program. DFT(B3LYP)/aug-cc-pVDZ method with the Grimme empirical dispersion correction modified by the Becke-Johnson damping function, and BSSE-corrected. cStructure retrieved from CSD and optimized with the CRYSTAL program (additionally underlined). d The first polymorph of the N:24DHB structure (REFCODE: DINRUP) with the OH group disorder removed (the ortho-OH group is farther away from the protonated oxygen from the carboxylic group). eSame as point (b) (REFCODE: DINRUP) but with the disordered OH group placed at the second ortho-position. fThe second polymorph of the N:24DHB cocrystal (REFCODE: DINRUP01). g Same as N:25DHB but measured at room temperature (REFCODE: PEKRUU). hIonic structure. iTwo different dimers of this type present in the structure.

bonded architecture based on synthons I, III′, and IV (Table 2, Figure 4d), is found in N:25DHB. The only structure in the studied series, in which a proton transfer takes place, is N:26DHB (Figure 4e). Similar to the majority of other nicotinamide cocrystals, synthon I is primarily formed here. As expected, the two ortho-hydroxyl groups from 26DHB are involved in intramolecular hydrogen bonding. Moreover, oxygen atoms from these hydroxyl groups are acceptors for protons from the amide fragment of N. 4923



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Figure 4. Structural motifs in cocrystals with nicotinamide: (a) N:23DHB, (b) N:24DHB-Ib (see Table 2 for explanation of the upper index b) (c) N:24DHB-II, (d) N:25DHB, and (e) N:26DHB.

Figure 5. Structural motifs in cocrystals with pyrazinamide: (a) P:23DHB, (b) P:24DHB, (c) P:25DHB, and (d) P:26DHB.

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Figure 6. Interaction energy values for selected hydrogen-bonded molecular complexes present in the analyzed cocrystal structures. Color coding: blue (left) − DFT(B3LYP)/aug-cc-pVDZ (GAUSSIAN), red (middle) − MP2/6-31G** (PIXEL), green (right) − DFT(B3LYP)/6-31G** (CRYSTALEXPLORER).

Figure 7. Percentage contributions to Hirshfeld surface of (a) nicotinamide and (b) pyrazinamide in the analyzed cocrystals with DHBs.

Accordingly, a motif strongest-stabilized in terms of interaction energy is synthon II and next I. In turn, IV, VI, and VII are characterized by medium energy values, while synthons III and III′ are weakest-stabilized. Regarding the strongest-bound dimers the most advantageous energies were obtained using GAUSSIAN, then with the CRYSTALEXPLORER approach, while the least favorable values were derived from the PIXEL

computations. The differences between the three approaches are less pronounced for medium-strength interactions. A comparison of relative contributions of electrostatic, dispersive, polarization and repulsion terms between PIXEL and CRYSTALEXPLORER (see Tables 3S and 4S in the Supporting Information) reveals that, while the electrostatic energy 4925



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Figure 8. Total interaction energy calculated for molecular complexes stabilized by π···π stacking (a) N:24DHB-I, (b) N:24DHB-II, (c) P:26DHB, and C−H···π interactions (d) N:23DHB (energy values are given in kJ·mol−1).

contributions are very much alike, other terms differ significantly. Importantly, in the analyzed cocrystals a heterodimer always constitutes the strongest-bound molecular complex, which is one of the primary factors supporting cocrystal formation. In the case of synthons I and II the respective synthon interaction energies are relatively robust, varying only within 10 kJ·mol−1 between different cocrystals. In contrast, the interaction strength describing synthon I′ is more variable, as it depends noticeably on the location of the hydroxyl group involved in the hydrogen bond. Thus, dimer interaction energies may differ here by up to 30 kJ·mol−1. Among the P cocrystals this interaction is strongest when the OH group is located at positions 4 or 5 at the acid aromatic ring, i.e., possibly far from the second OH group and the COOH function. In the case of N cocrystals I′ is present only in the second polymorph of N:24DHB and the respective interaction energy outnumbers that calculated for the P equivalent by about 6 kJ·mol−1. Interestingly, N:24DHB-II resembles P:25DHB in terms of synthons and their stabilization energies. In turn, the synthons encountered in the N:24DHB-I crystal structure (i.e., I, III, III′, IV) are alike those present in N:25DHB and are described by similar interaction energy values. All synthons can also be easily identified and compared among the studied series through the analysis of the closest contacts contribution to the Hirshfeld surface constructed either for N or P (see Figure 1S in the Supporting Information). The examination of partial contributions of particular contact types to HS (Figure 7) led to a number of remarkable conclusions. The percentage of the N···H contacts vs O···H is greater in the molecular complexes of P, whereas the opposite is observed for the N cocrystals. Obviously this is the result of two N atoms available for noncovalent interactions in P when compared to only one in N. Yet, the sum of hydrogen bonding-like interactions (i.e., the above-mentioned

N···H and O···H contacts) is similar throughout the whole series. However, the structural analysis indicates that more complex hydrogen-bonded patterns were found for the nicotinamide-containing cocrystals due to its greater flexibility than P, which was described earlier in the text. Finally, the contribution of the N···H contacts is lowest in N:26DHB because of the proton transfer present in its structure. Naturally, not only hydrogen bonding interactions contribute to the crystal network stability. As all used coformers are aromatic molecules, various dispersive interactions are also noticeable and essential to understand the formed crystal architectures. This is confirmed by the HS analysis indicating that, for instance, the C···C contribution to the respective HS area for N:24DHB-II, N:25DHB, P:23DHB, and N:26DHB, reflecting majorly π···π stacking, is higher than 10%. For the first three systems dimer interaction energies for molecules involved in π···π stacking range from −10 to −25 kJ·mol−1 (according to the CRYSTALEXPLORER results; see Figure 8 and Supporting Information). As both N and P possess nitrogen atoms in the aromatic rings, high contribution of C··· N to the HS area may also indicate some π···π stacking interactions. This is the case for N:24DHB-I, in which the C··· C interactions’ contribution to HS does not exceed 5%. However, when these are considered together with the C···N and C···O contacts, it gives more than 15% overall contribution to the HS area. Indeed, the analysis of dimer interaction energies reveals that for this particular structure the most energetically favorable stacking contacts are observed (e.g., −42 kJ·mol−1 between two acid molecules, see Figure 8). In turn, in the case of P:26DHB and N:23DHB, even though the molecules of P or N and acid form layered architecture, the offset between aromatic rings from the adjacent layers is high enough to reduce significantly contributions from the C···C contacts. Thus, in N:23DHB these are substituted by the greater contribution from the C···H contacts, which reaches 4926



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20%, being around two times higher than that derived for the remaining structures (Figure 7). It means that here the hydrogen-bonded network is further stabilized by C−H···π and C−H···C interactions (from −10 to −15 kJ·mol−1, see Figure 8d) rather than π···π stacking. In the case of P:26DHB both C···H and C···N contacts support additionally the crystal lattice stability. 3.5. General Discussion of the Studied Cocrystal Structures and Related Cohesive Energies. The structural studies indicate that, while nicotinamide or pyrazinamide molecules may define the formation of the main synthons, the overall structural network strongly depends on the dihydroxybenzoic acid type. This is because the orientation and the accessibility of the OH groups are critical factors determining the interaction geometry, thus the hydrogen bond network type and also the stability of the crystal architecture. Furthermore, in all the acids the ortho-OH group is locked in a six-membered intramolecular hydrogen bond motif, which leads to the decreased stabilization of other hydrogen bond interactions it is involved in. In the case of 26DHB, both OH groups are engaged in intramolecular contacts. Similarly, an intramolecular interaction is formed between the N1 atom and the amine group in the pyrazinamide molecule, which makes the amide group less flexible than that of nicotinamide (see Figure 3). Considering such restrictions and the above structural motif analysis, it appears that 24DHB, 25DHB, and the mobile amide group of N provide greatest flexibility in terms of molecular interconnections. First general conclusions regarding crystal network stability can be made on the basis of the so-called energy frameworks analysis (Figure 9). Such frameworks indicate the directionality and strength of main interactions present in a crystal lattice. In the case of the studied series the analysis shows that for the P cocrystals, as well as for N:24DHB-II, synthon II is clearly the most energetically advantageous one, constituting, major subunit building chains and layers. As can be seen in Figure 9 the presence of such a strongly bound synthon imposes less isotropic distribution of interactions in different directions. In contrast, in the cocrystals containing nicotinamide (excluding N:24DHB-II), in which the synthon II does not appear, more significant interactions are of similar strength and are quite uniformly distributed in space. This observation is well illustrated by the example of the N:24DHB polymorphs. In the case of N:24DHB-I interactions are in general relatively isotropically distributed along the X, Y, and Z directions (especially along X and Z), whereas for N:24DHB-II strongly stabilized molecular chains lead to the more pronounced directionality of interactions in the crystal lattice. Importantly, energy frameworks reflect to some extent crystal mechanical properties.62 Diagrams showing separately electrostatic and dispersive energy frameworks are available from the Supporting Information. Additionally, the cocrystal cohesive energies and the corresponding cohesive energies of cocrystal component structures were evaluated. In all the cases, cocrystal cohesive energies are more advantageous than the sum of the respective single component crystal cohesive energies (Tables 3 and 4), which supports the cocrystal formation. As presumed, pyrazinamide cocrystals are less energetically favored than their nicotinamide equivalents. The least stabilizing cohesive energy among the studied systems is observed for P:23DHB. Interestingly, the 23DHB acid also forms the least energetically favorable cocrystal with N. This is

Figure 9. Total energy frameworks generated for the studied cocrystals. Line thickness indicates the interaction energy value (the thicker the line the greater the energy). Views are presented along the X (2nd column), Y (3rd column), and Z (4th column) axes.

attributed to the arrangement of the hydroxyl groups in the acid molecule, which reduces the number of beneficial intermolecular interaction patterns. For instance, the only hydrogenbonded motif that exists in the structure of P:23DHB is a single ribbon (based on synthons II and I′), while the N1 atom is not involved in any significant intermolecular contacts. In the case of P:26DHB, a hydrogen-bonded tape motif is formed, which involves three types of synthons and results in only slightly better stabilized crystal lattice (by about 4 kJ·mol−1). It should be noted, however, that the 26DHB acid is a specific case, being the most acidic species among the chosen DHB series (Table 5). On the other hand, N is much more basic than 4927



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Table 5. ΔpKa Values Characterizing Cocrystal Components As Referenced to Nicotinamide (pKa = 3.35) or Pyrazinamide (pKa = 0.50)a

Table 3. Cohesive Energy Values (Ecoh) Computed for Optimized Crystal Structures Using Either CRYSTAL or PIXEL Programsa cocrystal

−1 ECRY coh /kJ·(2 mol)

−1 EPIX coh /kJ·(2 mol)

N:23DHB N:24DHB-Ib,c N:24DHB-Ib,d N:24DHB-IIb,e N:25DHB N:25DHBRTb,f N:26DHBg P:23DHB P:24DHB P:25DHB P:26DHB

−254.8 −273.7 −295.5 −270.2 −274.4 −271.5 −653.1 −237.0 −256.7 −253.0 −240.8

−226.4 −230.0 −250.2 −234.6 −240.2 −235.0

P%

cocrystals with N

71 70 70 70 71 71 75 73 72 73 75

−210.0 −230.1 −236.4 −219.4

cocrystals with P

DHB component

pKa

ΔpKa

type

ΔpKa

type

23DHB 24DHB 25DHB 26DHB

2.96 3.32 3.01 1.30

+0.39 +0.03 +0.34 +2.05

neutral neutral neutral ionic

−2.46 −2.82 −2.51 −0.80

neutral neutral neutral neutral

a

ΔpKa = pKN/P − pKDHB . a a

species, the cohesive energy of N:26DHB is particularly high in amplitude. The nicotinamide molecule and 2,4- and 2,5-dihydroxybenzoic acids are the components which have potential to form the best stabilized cocrystals among the studied compounds. The nicotinamide molecule is more flexible than pyrazinamide, as the rotation of the amide group is less constrained. It may adopt different structural conformations and, therefore, more effectively utilize the intermolecular contacts when compared with pyrazinamide. 24DHB’s and 25DHB’s advantage over the other acid molecules is the aforementioned arrangement of the hydroxyl substituents which guarantees the accessibility of these two hydrogen-bond-donor sites. Indeed, the P:24DHB and P:25DHB crystal structures are characterized by comparable cohesive energy and are the most stable ones among the P cocrystals, whereas both polymorphs of N:24DHB as well as N:25DHB constitute the most energetically favored crystal structures in the whole series. Furthermore, the flexibility of N, and the mentioned accessibility of the hydroxyl groups of 24DHB, resulted in the only one pair of polymorphs observed for the studied cocrystals.

a

Note the energies are given per two ASU contents together. Packing coefficient (P) was estimated with the OLEX2 program.87 bStructure retrieved from CSD and optimized with the CRYSTAL program (additionally underlined). cThe first polymorph of N:24DHB structure (REFCODE: DINRUP) with the OH group disorder removed (the ortho-OH group is farther away from the protonated oxygen from the carboxylic group). dSame as point (b) (REFCODE: DINRUP) but with the disordered OH group at the second orthoposition. eThe second polymorph of N:24DHB cocrystal (REFCODE: DINRUP01). fSame as N:25DHB but measured at room temperature (REFCODE: PEKRUU). gIonic structure.

P. These two facts result in a ΔpKa significantly higher for N:26DHB than for all other cocrystal component pairs in the studied set. ΔpKa can generally be considered as a useful indicator for the formation of cocrystals versus salts when acids and bases are the reactant constituents.88 According to that concept, ΔpKa value (as computed in Table 5) greater than 2 or 3 is a typical threshold for salt formation. Yet, there are also other criteria based on experimental observations. For instance, Johnson & Rumon89 proposed a higher limit, with ΔpKa > 3.75 for possible proton transfer. Although the ΔpKa values are usually reliable indicators of salt formation when ΔpKa > 3, we stress that the ΔpKa range 0−3 is rather ambiguous. Thus, cocrystal formation is expected when ΔpKa < 0, but both neutral-type and salt-type crystals can be formed between 0 and 3. In the studied series ΔpKa = 2.05 occurred to be sufficient to indicate a proton transfer observed in N:26DHB. All other values are close to 0, or negative; therefore, they support the observed neutral cocrystal forms. Because of the presence of charged

4. SUMMARY In the studied systems the major factor governing the main synthons formation is the mutual basic character of proton acceptors in pyrazinamide and nicotinamide, i.e., the carbonyl fragment and aromatic nitrogen atoms. Regarding the acid molecules, certainly the competitive affinities of the COOH and OH groups toward the N-donor compounds are crucial, including the relative location of all functions. The carboxyl group, being the most acidic moiety, binds preferably to the strongest base, thus either to the amide group in the case of pyrazinamide forming the most energetically favored synthon II, or to the pyridine N atom of the nicotinamide molecule leading most often to motif I. In

Table 4. Crystal Cohesive Energies Calculated for CRYSTAL-Optimized Single Cocrystal Component Structures on the Basis of Structural Data Provided by CSDa crystal structure 23DHB 24DHB 25DHB 26DHB-Ib 26DHB-IIc Nα Pα Pβ

CSD REFCODE CACDAM ZZZEEU02 BESKAL LEZJAB LEZJAB01 NICOAM01 PYRZIN15 PYRZIN18

space group P1̅ P21/n P21/n Pna21 P21/c P21/c P21/n P21/c

T/K

−1 ECRY coh / kJ·mol

−1 EPIX coh / kJ·mol

ref

−118.6 −132.6 −131.0 −129.1 −113.6 −121.3 −106.7 −109.0

−113.8e −116.2 −122.0 −113.5 −103.0 −115.4 −88.6 −103.7

Okabe & Kyoyama, 200134 Parkin et al., 200731 Haisa et al., 198235 Gdaniec et al., 199432 MacGillivray & Zaworotko, 199433 Miwa et al., 199948 Nangia & Srinivasulu, 2006f Cherukuvada et al., 201046

d

RT 100 RT RT RT 150 100 100

e

Computations done with CRYSTAL and PIXEL programs N/Pα/β means either α or β phase for nicotinamide or pyrazinamide; T − measurement temperature as reported. bFirst polymorph. cSecond polymorph. dRT − room temperature. eAveraged energy. fCSD private communication.

a

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Hirshfeld surfaces and Hirshfeld fingerprint plots generated for the pyrazinamide cocrystals, dispersive energy frameworks generated for the studied cocrystals, and a comment on the energy frameworks for the studied cocrystals to all the following figures (PDF)

general, pyrazinamide, characterized by greater rigidity than nicotinamide, creates more preserved basic structural motifs and less complex crystal architectures. This is because of the hampered rotation of the amide group involved in the intramolecular hydrogen bonding interaction, which makes P less capable to adjust to the other molecules constituting a crystal lattice. In turn, in the case of nicotinamide there are two distinct energy minima in the amide group rotation energy scan, which differ by about 4.6 kJ·mol−1. Thus, N can adopt almost equally well both syn and anti conformation in a crystal. Consequently, crystal lattice stabilization energy values for the cocrystals formed with the corresponding dihydroxybenzoic acid moieties are more advantageous for nicotinamide, whereas patterns created by pyrazinamide are more predictable. In the latter case, as illustrated by the energy frameworks, preferred formation of synthon II, significantly outweighing other motifs in terms of interaction energy (exceeding −80 kJ·mol−1), leads to molecular patterns of certain directionality of interactions in a crystal structure, which is opposite to more energetically uniform motifs, and thus more isotropic crystal lattice, in the case of N cocrystals. Another important factor determining crystal architecture concerns the accessibility of hydroxyl groups in the aromatic ring of the benzoic acid. Although the lattice energies of the analyzed acid monocomponent crystals are quite alike, the energetic differences are clearly visible in their cocrystal structures. The most complex crystal architectures are formed by 2,4- and 2,5-dihydroxybenzoic acids, while 2,3-dihydroxybenzoic acid limits the crystal network most notably. Therefore, cocrystals containing N and 24DHB or 25DHB exhibit the most advantageous cohesive energy values (excluding the salt-like structure of N:26DHB), and also much greater variety of structural patterns and energetically significant intermolecular contacts than the remaining structures. Furthermore, N:24DHB is the only case when polymorphic structures are encountered. The mutual location of hydroxyl groups also determines the acidity of a given acid molecule. In the case of N:26DHB the difference of the pKa values of both components is high enough to stimulate proton transfer between N and 26DHB leading to the only salt type structure among the series. Despite the fact that in all studied cocrystals main structural motifs are based on hydrogen bonds being in accord with the Etter’s rules, the dispersive forces surely cannot be neglected. This is especially true for P:23DHB, N:24DHB-II, N:25DHB, and N:26DHB cocrystals, where there is a notable contribution of π···π stacking interactions to the total lattice energy value. Finally, it should be noted that in all the cases the best stabilized molecular synthon is a heterodimer, while cocrystal cohesive energies are more favorable than that of the respective single component crystal structures, which supports the cocrystal formation.

■

Accession Codes

CCDC 1554966−1554971 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*(K.N.J.) E-mail: [email protected]. *(K.W.) E-mail: [email protected]. ORCID

Katarzyna N. Jarzembska: 0000-0003-4026-1849 Sunil Varughese: 0000-0003-0712-915X Radosław Kamiński: 0000-0002-8450-0955 Maura Malinska: 0000-0002-7138-7041 Krzysztof Woźniak: 0000-0002-0277-294X Author Contributions #

K.N.J. and A.A.H. contributed equally.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS K.N.J. and A.A.H. would like to acknowledge the PRELUDIUM grant (2011/03/N/ST4/02943) of the National Science Centre in Poland for financial support. The Wrocław Centre for Networking and Supercomputing (Grant No. 285) and the Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw (G33-14) are gratefully acknowledged for providing computational facilities. S.V. thanks DST, New Delhi, for the start-up research grant. The authors would like to thank Mark A. Spackman (Perth, Australia) for his substantial help with the newest version of the CRYSTALEXPLORER program.

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REFERENCES

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00868. Experimental details regarding crystallographic data, interaction energy values calculated for selected hydrogen-bonded synthons, details on thermal analysis, energy contributions to the total interaction energy computed with the CRYSTALEXPLORER and PIXEL programs, 4929



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