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Molecular salts of 2,6-dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: Crystal structures, spectral properties and Hirshfeld surface analysis
Accepted Manuscript Molecular salts of 2,6-dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: Crystal structures, spectral properties and Hirshfeld surface analysis K. Anand Solomon, Olivier Blacque, Ramanathan Venkatnarayan PII:
S0022-2860(16)31374-6
DOI:
10.1016/j.molstruc.2016.12.055
Reference:
MOLSTR 23253
To appear in:
Journal of Molecular Structure
Received Date: 10 September 2016 Revised Date:
20 December 2016
Accepted Date: 21 December 2016
Please cite this article as: K.A. Solomon, O. Blacque, R. Venkatnarayan, Molecular salts of 2,6dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: Crystal structures, spectral properties and Hirshfeld surface analysis, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2016.12.055. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Molecular salts of 2,6-dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: crystal structures, spectral properties and Hirshfeld surface analysis
a*
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K. Anand Solomon a* , Olivier Blacqueb , Ramanathan Venkatnarayanc Department of Chemistry, School of Engineering, Dayanand Sagar University, Kudlu Gate,
Bangalore 560068 b
Department of Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich – Switzerland Dept. of Chemistry, SASTRA University, Thanjavur 613104, Tamil Nadu, India
Corresponding author: Tel No.: +919845522791 E-mail address: [email protected]
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ABSTRACT
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In the present study, two molecular complexes of 2,6-DHB with pharmaceutically active nutraceuticals i.e. nicotinic acid (NA) and nicotinamide (NIC) have been synthesized and preliminarily characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and FT-IR spectroscopy. Finally the crystal structures were solved by single crystal X-ray diffraction and the structures were analyzed in terms of supramolecular interactions. The salt 1 crystallizes in the monoclinic space group Cc, with a = 10.1503(1) Å, b = 12.3821(1) Å, c = 9.5291(1) Å, β = 94.343(1)°, V = 1194.20(2) Å3, Z = 4. The salt 2 crystallizes in monoclinic space group P21/n, with a = 7.0098 (1) Å, b = 12.5495 (1) Å, c = 13.4048 (1) Å, β = 92.746 (1)°, V = 1177.86 (2) Å3, Z = 4. The molecular packing of both salts are stabilized by N+−H···O–, O−H···O–, N−H···O and O−H···O hydrogen bonding interactions. DFT calculations substantiate the features of crystal structures. The Hirshfeld surfaces and the associated 2D fingerprint plots were investigated which revealed that more than two-third of close contacts were associated with relatively weak H···H, C···H and H···C interactions. The use of 3-D Hirshfeld surfaces in combination with 2-D fingerprint plots revealed that these weak interactions play major role in molecular crystal packing. Keywords: molecular salts, supramolecular hetero-synthon, 3-D Hirshfeld surface, 2-D fingerprint plots. 1. Introduction
Crystal engineering comprises an understanding of intermolecular interactions which govern the crystal packing, thus allowing the design of new solid forms with improved physical and chemical properties [1-5]. An organic crystal can be regarded as an ultimate supramolecule 1
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which is not only assembled via molecular recognition (supramolecular assembly) but also stabilized by weak, non-covalent interactions (crystal engineering). Salt formation is a widespread multicomponent approach to improve the physicochemical properties of the active pharmaceutical ingredients (APIs) in the pharmaceutical industry [8-10]. They have been shown
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to modulate the solubility and bioavailability of APIs [11-13]. Even hydrochloride salts of APIs can offer improved solubility and stability but hygroscopicity is a drawback of the product salts [14, 15]. A crystal engineering approach in selection of acid or base for a given API to make salts or co-crystals is reported in the literature [16-18]. Extensive research has been focused in
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the crystal engineering of systems having pyridine moieties i.e., nicotinic acid (NA), nicotinamide (NIC), isoniazid and isonicotinamide [19, 20] due to their broad spectrum of
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biological activities. NA is a potent lipid-modifying agent which decreases total cholesterol, LDL cholesterol, triglycerides and increase HDL cholesterol [21, 22]. NA is also reported to reduce coronary artery disease [23]. NIC is precursor to nicotinamide adenine dinucleotide phosphate (NADP), which is required for ATP synthesis, oxidation-reduction reactions, and ADP-ribose transfer reactions [24]. 2,6-DHB is strong acid because both hydroxyl groups form intramolecular hydrogen bonding with the carboxylic functionality [25]. This is reflected in the
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fact that both the molecular complexes of 2,6DHB exist as salts. The ∆pKa (∆pKa = pKa (base) pKa (acid)) criterion plays a major role in the acid-base reactions; if the ∆pKa is greater than 3 then salt formation is expected [26, 27]. Y. H. Luo et al. have reported the application of Hirshfeld surfaces analyses for the investigation intermolecular interactions of p-hydroxybenzoic
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acid [28].
In recent years, numerous techniques have been introduced to investigate the intermolecular
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interactions in crystal structures qualitatively and quantitatively, namely conformational similarity index for proteins [29] graph set analysis for hydrogen bonding [30], Hirshfeld surface analysis [31, 32] and so on. These methods are performed by specialised computer aided programs ESCET [33], COMPACK [34], Crystal Explorer [35] and dSNAP [36] respectively. The graphical tools based on Hirshfeld surface and the two dimensional (2D) fingerprint plots offer considerable promise for exploring packing patterns and intermolecular interactions in the molecular crystals [37].
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2,6-DHB - a versatile co-crystal former for APIs having N-heterocycles due to its hydroxyl and carboxyl functional groups, usually results in binary crystalline phases and robust supramolecular architectures. Thus an investigation of its supramolecular synthons pattern is of significant importance. Hence, the primary objective of the current study is the investigation of
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the supramolecular synthons of the two molecular slats of 2,6-DHB (scheme 1) for the purpose
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OH
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of understanding the influence of different N-heterocycles as co-crystal formers.
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NH 2
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Scheme 1 Structure of molecular salts 1 and 2
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Hence in this work, we have studied the co-crystallization of 2,6-DHB with a series of Nheterocycles: nicotinic acid (NA), isonicotinic acid (INA), nicotinamide (NIC), isonicotinamide (IN) and 2-aminopyridine (2-AP) and we obtained two molecular salts 2,6-DHB−NA (1) and
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2,6-DHB−NIC (2). We characterized the structures of both molecular salts by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), single-crystal X-ray diffraction and FT-IR spectroscopy. The Hirshfeld surface and 2D fingerprint plot of 2,6-DHB in both the molecular salts were analyzed to investigate the influence of different N-heterocycles on the intermolecular interactions of the 2,6-DHB molecule. 2. Experimental 2.1. Materials 3
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All the starting materials i.e. 2,6-DHB (purity > 99.8%, CAS registry number: 303-07-1), NA (purity > 99.8%, CAS registry number: 59-67-6) and NIC (purity > 99.8%, CAS registry number: 98-92-0) were purchased from Sigma Aldrich (India) Ltd. Methanol with HPLC grade
2.2. Synthesis and growth of molecular salts 1 and 2
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purity was obtained from Molychem chemicals (India).
A 1:1 stoichiometric ratio of 2,6-DHB (50mg, 0.324 mmol) and NA (40mg, 0.324 mmol) were dissolved in methanol at 60° C for 10 minutes and the resulting homogeneous solution was kept undisturbed at ambient temperature for slow evaporation. Colorless block-shaped crystals of
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1 suitable for single crystal X-ray analysis were obtained after 2 days (yield 80%, based on 2,6DHB).
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The same procedure was followed for obtaining salt complex 2 by using NIC (40mg, 0.324 mmol) in lieu of NA. Colorless prism-shaped crystals of 2 were obtained after 3 days (yield 75%, based on 2,6-DHB). Various solvents like methanol, ethanol, acetonitrile, and acetone were tried for crystallization to obtain good quality of crystals. Among the four solvents used methanol was found to be the best solvent for growth of these crystals. 2.3. Powder X-ray Diffraction (PXRD)
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The PXRD patterns of all the samples were collected on a Bruker D8 Advance diffractometer (Germany) with 2.2 KW Cu anode, Ceramic X-ray tube source and Lynx Eye detector. The samples were scanned 4° and 80° in 2θ with a step size of 0.02°. 2.4. Differential scanning calorimetry (DSC)
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Thermal analyses of the starting components and the molecular salts 1 and 2 were performed on a differential scanning calorimeter (DSC 200 F3, Netzsch, Germany). The instrument was
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equipped with linear small compressor for cooling. The crystals (3-5 mg) were crimped in aluminium crucibles and scanned at a heating rate of 10°C/min in the range 30-250°C under dry nitrogen atmosphere (flow rate of 50 mL/min). The data were collected Proteus software version 5.2.1.
2.5. Infrared spectroscopy (FTIR) A Bruker Alpha-T Fourier transform infrared spectrophotometer was used record the IR spectra of the samples (sample concentration is 2 mg in 20 mg of KBr). The spectra were
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recorded over the spectral range 4000 to 600 cm−1 with resolution of 2 cm-1. Data were analyzed using OPUS software version 6.5. 2.6. Single crystal X-ray diffraction (SCXRD) Single-crystal X-ray diffraction data (Table 1) were collected at 183(2) K on an Agilent
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Technologies Super Nova Atlas area-detector diffractometer using a single wavelength Enhance X-ray source with Mo Kα radiation (λ = 0.71073 Å) [38] from a micro-focus X-ray source and an
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Oxford Instruments Cryojet XL cooler.
Table 1 Crystallographic data of the molecular salts 1 and 2 5
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The selected single crystals were mounted using polybutene oil on a flexible loop fixed on a goniometer head and immediately transferred to the diffractometer. Pre-experiment, data collection, data reduction and analytical absorption correction [39] were performed with the program suite CrysAlisPro [40]. The structure was solved by direct methods using SHELXS97
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[41]. The structure refinements were performed by full-matrix least-squares on F2 with SHELXL97 [41]. PLATON [42] was used to check the result of the X-ray analyses. All programs used during the crystal structure determination process are included in the WINGX software [43]. All the H positions bound to C atoms were calculated after each cycle of
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refinement using a riding model C−H = 0.93 Å and Uiso(H) = 1.2Ueq(C). All the H atoms bound to N and O atoms were located in difference Fourier maps and freely refined. The selected bond
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lengths and bond angles for compounds 1 & 2 are listed in Table 2, the relevant hydrogen bond
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parameters are provided in Table 3. In both the tables the ab-initio measurements are included.
Table 2 Selected bond lengths (Å) and angles (°) for 1 & 2
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Symmetry codes: (i) x+1/2, y+1/2, z+1 (ii) x, y+1, z (iii) x-1/2, -y-1/2, z-1/2
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2.7. Theoretical calculation
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Table 3 The hydrogen bonding geometrical parameters for 1 and 2
Molecular parameters as measured from XRD are very well supported by the DFT calculations carried out at B97D/6-311++G(d,p) level of theory. These are summarized in tables 2 and 3. Molecular Hirshfeld surfaces are generated by CrystalExplorer [35] computer program. Hirshfeld surface is an easily interpretable visualization of a molecule within its environment.
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The 2D fingerprint maps obtained from the reduced Hirshfeld surfaces provide the full distribution of intermolecular interactions. The principle of Hirshfeld surfaces are reported elsewhere [44-46]. 3. Results and discussion
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Salts can be distinguished from the co-crystals by the location of the proton between an acid and a base. The proton transfer can be evaluated from their SCXRD and FT-IR spectroscopic analyses. Salt formation was revealed from the single-crystal SCXRD analysis of the molecular
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salts 1 and 2 where the transferred hydrogen was located from a difference Fourier map [47]. 3.1. PXRD analysis
Powder X-ray diffraction is a fingerprint characterization technique for identification of new solid phases such as salts and co-crystals [48]. Both the multi-component salts display a unique crystalline PXRD patterns in comparison to the starting components (Fig. 1).
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Fig. 1 PXRD pattern of 2,6-DHB, 1 and 2
The powder X-ray diffraction of salt complex 1 exhibited characteristic reflections at about 2θ 14.22° and 28.68°. The salt complex 2 exhibited characteristic reflections at about 2θ 14.94°,
multicomponent solid forms. 3.2. Single crystal X-ray analysis
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16.42°, 19.21°, 26.55°, 27.68°, 29.02° and 39.76°, This indicates the formation of new
3.2.1. Description of the crystal structure of molecular salt 1(2,6-DHB–NA) The molecular salt 1 crystallizes as colorless block-shaped crystals. The structural
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determination shows 1 forms a 1:1 (2,6-DHB–NA) molecular salt in the monoclinic Cc space group with Z = 4, the asymmetric unit of 1 consists of one mono-protonated NA and one mono-
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anion of 2,6-DHB (Fig. 2).
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Fig. 2 Asymmetric unit of salt 1 showing atom-labeling scheme. In 1 the –COOH group of 2,6-DHB is ionized due to proton transfer to the pyridine nitrogen
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atom of the NA moiety while the –OH groups remain unionized. Proton transfer from the – COOH group (atom O3) to the pyridine ring (atom N1) is evidenced by the difference between the C–O bond distances C7–O3 = 1.273(8)Å, and C7–O4 = 1.267(9) Å of the carboxylate group with the ∆DC-O value of 0.006 Å. The relatively small ∆DC-O value which is expected for
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carboxylate group [49]. The protonation of NA on N1 site is reflected in the change in the bond angle. The angle at un-protonated ring N atom is 117.5° [50], while for protonated ring N atom the angle (C9-N1-C10) is 122.53(6)°. The torsion angles O1–C2–C3–C4 and O2–C6–C5–C4 are
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178.89(7)°, and 178.73(7) ° respectively. In this regard both the phenol groups are nearly in the same plane as the benzene ring of the anion. The torsion angle O5–C13–C8–C9 is 175.51(7)° indicates that the acid group is nearly in the same plane as pyridinium ring plane. In the crystal, the 2,6-DHB anion and pyridinium moiety of NA form a dimer unit by N1–H13···O3 and C10– H10···O4 hydrogen bonding interactions through R22(7) heterosynthon supramolecular ring
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bond interactions (Fig. 3).
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motif, the 2,6-DHB molecule also forms intramolecular O1–H1···O3 and O2–H2···O4 hydrogen
Fig.3 N+–H···O–, O–H···O and O–H···O– hydrogen bonding patterns in the basic supramolecular packing unit of 1 9
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The dimer unit then connects to two other units through O–H···O hydrogen bonding synthons, which involve –COOH and –OH functional groups. The overall crystal packing results
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in extended helical type supramolecular arrangement as shown in Fig. 4.
Fig. 4 The overall crystal packing of salt 1 resulting in helical type supramolecular architecture 3.2.2. Description of the crystal structure of molecular salt 2 (2,6-DHB–NIC)
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The molecular salt 2 crystallizes as colorless prism-shaped crystals. The structural determination shows 2 forms a 1:1 (2,6-DHB–NIC) molecular salt in the monoclinic P21/n space group with Z = 4, with the asymmetric unit consisting of one monocation of NIC and one
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monoanion of 2,6-DHB (Fig. 5).
Fig. 5 Asymmetric unit of salt 2, showing atom-labeling scheme. 10
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Proton transfer is evidenced by the difference between the C–O bond distances C7–O4 = 1.269(11) Å, and C7–O3 = 1.263(11) Å of the carboxylate group with the ∆DC-O value of 0.006 Å. The relatively small ∆DC-O value which is expected for carboxylate group [49].
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protonation of NIC on N1 site is reflected in the change in the bond angle. The angle at
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unprotonated ring N atom is 118.56(13)° [51], while for protonated ring N atom the angle (C9N1-C10) is 122.31(8)°. The torsion angles O1–C2–C3–C4 and O2–C6–C5–C4 are 179.68(9)°, and 176.85(9)°, respectively. In this regard both the phenol groups are nearly in the same plane as the benzene ring of the anion. The torsion angle O5–C13–C8–C12 is 167.98(9)° indicates that
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the amide group deviates by 12.02(9)° from the pyridinium ring plane. The crystal packing is mainly stabilized by N+–H···O– charge-assisted hydrogen bonds (N1–H6···O4 and N1–H6···O3)
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and also N–H···O neutral hydrogen bonding interactions (N2–H7···O2 and N2–H8···O1) (Fig.
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Fig. 6 N+–H···O–, N–H···O and O–H···O– hydrogen bonding patterns in the basic supramolecular packing unit of 2 The intramolecular charge-assisted O–H···O– hydrogen bonding interactions also stabilizing the molecular packing (O1–H1···O3 and O2–H2···O4). The deprotonation of 2,6-DHB leads to a boost of supramolecular synthons ability. The overall crystal packing resulted in the layered type of supramolecular architecture (Fig. 7).
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Fig. 7 The overall crystal packing of salt 2 resulting in layered type supramolecular arrangement 3.3. FT-IR spectral analysis
FT-IR spectroscopy is a widely used technique in the characterization of the formation of new solid phases and an excellent tool to distinguish the salts from co-crystals, especially when compounds having carboxylic acid group are used as a coformers [29]. The carbonyl (C=O) IR
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absorption frequency of carboxylic acid in 2,6-DHB observed at 1685 cm–1 which was absent in both the salts 1 and 2. Moreover the appearance of two characteristic carboxylate IR absorption vibrations at 1584 and 1345 cm–1 for 1 and 1587 and 1340 cm–1 for 2 due to asymmetric and symmetric O–C–O stretch respectively confirmed the proton transfer from the –COOH group in
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2,6-DHB [52]. The formations of salts are further supported by the appearance of strong bands at 1633 cm–1 for 1 and 1631 cm–1 for 2, which can be assigned to C=N vibrations characteristic of
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the quaternary nitrogen atom in a heterocyclic ring [53]. This strong C=N band due to strong ammono-aldehyde character of the pyridine ring, acquired as a result of quaternization was absent in both NA and NIC [54]. The FT-IR spectra of 2,6-DHB, 1 and 2 are shown in Fig. 8.
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Fig. 8 FT-IR spectra for 2,6-DHB, salt 1 and salt 2 3.4. Thermophysical properties
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in their DSC pattern (Fig. 9) .
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The two molecular complexes of 1 and 2 displayed an increased the thermal stability as in
Fig. 9 DSC thermograms showing the melting behavior of 2,6-DHB, 1 and 2
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The samples 2,6-DHB, 1 and 2 melted at 173.5°C, 186.5°C and 191.3°C with melting enthalpy of 90.94, 244.1 and 311.6 J/g respectively. The relation between enthalpy and melting
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temperature is shown in Fig. 10.
Fig. 10 Graph showing the relation between melting temperature and enthalpy of 2,6-DHB, 1 and 2
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The enthalpy of both the salts increased due to higher melting temperatures [55]. Therefore the salt formation increased both melting point and melting enthalpy. In case of 2,6-DHB, there is a noticeable degradation peak at 103.3 °C (∆H = 54.03 J/g) observed during heating, where as in case of molecular salts 1 and 2 no endothermic peaks related to similar degradation is
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observed. Both the salts are stable from 30 °C up to their corresponding melting temperature, which suggests the salts are anhydrous and homogeneous. Therefore the salts of 2,6-DHB of the
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present study demonstrated an increased level of thermal stability. 3.5. Hirshfeld surface analysis Each molecule in the asymmetric unit of a given crystal structure will have unique 3D Hirshfeld surface and 2D fingerprint map. Therefore a direct comparison can be made between 2,6-DHB molecules in different environments. Hirshfeld surfaces provide a three-dimensional picture of close contacts in a crystal, and these contacts can be summarized in a fingerprint map [56]. The distance from the Hirshfeld surface to the nearest atoms outside and inside the surface are characterized by the quantities de and di, respectively. The dnorm is a normalized contact 14
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distance based on de and di is defined as dnorm= (di - rivdW)/ rivdW + (de- revdW)/ revdW, symmetric in de and di with rivdW and revdW being the van der Waals radii of atoms. When dnorm is mapped on the Hirshfeld surface, close intermolecular distances are characterized by two identically colored regions, even if these occur on different molecules. The dnorm surface highlights both the donor
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and acceptor and it is therefore a versatile technique for analyzing the intermolecular interactions, such as hydrogen bonding interactions as well as weaker C–H···π interactions. The 3D Hirshfeld dnorm surfaces and 2D fingerprint maps of 2,6-DHB in molecular salts 1 and 2 are shown in Fig.11 and Fig.12 respectively, they clearly show the similarities and
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differences of the influences of the two different co-formers on the intermolecular interactions of
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the 2,6-DHB molecule.
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Fig. 11 3D dnorm surfaces of 2,6-DHB in molecular salts 1 (a) and 2 (b)
Fig. 12 2D fingerprint plots of 2,6-DHB in molecular salts 1 (a) and 2 (b)
The larger red circular regions on dnorm surfaces represent the strong hydrogen bonding interactions. The small red regions on the surfaces are corresponding to the C–H···π interactions. 15
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The pale yellow-green color points in the 2D fingerprint maps are corresponding to short contacts H···H, H···C and H···O interactions. For the molecular salt 1, N–H···O and O–H···O hydrogen bonding intermolecular interactions appear as two small spikes (upper left spike is sharp and lower right spike is broad) in the 2D fingerprint map, which have the most significant
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contribution to the total Hirshfeld surfaces of 1, comprised of 45.2%. The H–H interactions, which are appeared in the middle of scattered points in the 2D fingerprint map, comprises of 26.9% of the total Hirshfeld surfaces. The C–H···π interactions also have a relatively significant contribution to the total Hirshfeld surfaces of molecular salt 1, comprised of 9.4%, as was
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indicated by the “wings” in the upper left and lower right of the 2D fingerprint map. Apart from those above interactions, the presence of π···π (C–C), lone-pair···π (O–C) and lone-pair···lone-
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pair (O–O) interactions are observed and summarized in Table 4.
Table 4 Summary of the various contact contributions to the 2,6-DHB Hirshfeld surface area in molecular salts 1 and 2
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The Hirshfeld surfaces analysis for 2,6-DHB in molecular salt 2 is similar to 1. The N– H···O and O–H···O hydrogen bonding intermolecular interactions still have the most significant contribution to the total Hirshfeld surfaces of molecular salt 2, comprised of 40.4%, a little smaller than that in 1, then followed by H–H interactions (32%), little larger than that of
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molecular salt 1. The C–H···π interactions contribute 7.9% to the total Hirshfeld surfaces, a little smaller than that of molecular salt 1. The other contacts are summarized in Table 4.
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Salt formation in case of 2,6-DHB is not surprising as a CSD analysis revealed that almost all the multicomponent systems of 2,6-DHB, salt form is preferred. To explain why 2,6-DHB (pKa = 1.22) forms crystalline molecular salts with NA and NIC, we calculated ∆pKa values for both the salts 1 and 2 and other known crystal structures containing pyridine moieties and 2,6-DHB (Table 5). It has been observed that when the ∆pKa exceeds 2 (Table 5, Entries 2 & 4) salts were obtained.
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S.No.
Compound pKa
∆pKa Crystalline form
NA 4.85a 3.63 Salt* 1 NM 3.35a 2.13 Salt* 2 a PHZ 1.4 2,6-DHB0.22 Co-crystal57 PHZ 7 MEL 5.6a 8 2,6-DHB 4.38 Salt58 MEL a Obtained from Merck Index, *present study Table 5 ∆pKa values for complexes of 2,6-DHB
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1 2 3 4 5 6
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It has been reported in the literature that 2,6-DHB forms a co-crystal with phenazine [57] when the ∆pKa = 0.22, where as 2,6-DHB forms a salt with melamine [58] when ∆pKa = 4.38 (Table 5, Entries 6 & 8). 4. Conclusions
To summarize, we have reported synthesis, crystal growth, X-ray crystal structure analysis
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and the Hirshfeld surfaces analyses of two supramolecular complexes of 2,6-dihydroxybenzoic acid with nicotinic acid and nicotinamide respectively. The two salt complexes obtained by supramolecular synthons, mainly stabilized hydrogen bonding, H–H, C–H···π and lone-pair–π interactions. The analysis of 2D fingerprint maps revealed that N–H···O and O–H···O hydrogen
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bonding intermolecular interactions are more prominent in both the salts. The formation of complexes were further characterized and confirmed by FT-IR analysis. The crystal structures
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are stabilized by both charge-assisted N+−H···O–, O−H···O– as well as neutral N−H···O and O−H···O hydrogen bonding interactions. Formations of pyridinium ion and carboxylate anion were confirmed by FT-IR analysis. The molecular salts also displayed higher thermal stability compared to the starting materials. Acknowledgments KA thanks the management of Dayananda Sagar University for the financial Support and encouragement. VR would like to acknowledge SASTRA University for the computational infrastructure. 17
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Supporting Information Available Crystallographic data for the structural analysis have been deposited with Cambridge Crystallographic Data Center, CCDC Nos. 923884 for 1, and 923883 for 2. These data can be obtained
free
of
charge
from
the
Cambridge
Data
Centre
via
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www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic
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The paper reports the analysis of two salts of an N-heterocycle The salts have been characterized by various analytical techniques DFT calculations substantiates the crystal structure
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3-D Hirshfeld surfaces analysis in combination with 2-D fingerprint plots revealed that
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weak interactions play major role in molecular crystal packing.
S0022-2860(16)31374-6
DOI:
10.1016/j.molstruc.2016.12.055
Reference:
MOLSTR 23253
To appear in:
Journal of Molecular Structure
Received Date: 10 September 2016 Revised Date:
20 December 2016
Accepted Date: 21 December 2016
Please cite this article as: K.A. Solomon, O. Blacque, R. Venkatnarayan, Molecular salts of 2,6dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: Crystal structures, spectral properties and Hirshfeld surface analysis, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2016.12.055. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Molecular salts of 2,6-dihydroxybenzoic acid (2,6-DHB) with N-heterocycles: crystal structures, spectral properties and Hirshfeld surface analysis
a*
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K. Anand Solomon a* , Olivier Blacqueb , Ramanathan Venkatnarayanc Department of Chemistry, School of Engineering, Dayanand Sagar University, Kudlu Gate,
Bangalore 560068 b
Department of Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich – Switzerland Dept. of Chemistry, SASTRA University, Thanjavur 613104, Tamil Nadu, India
Corresponding author: Tel No.: +919845522791 E-mail address: [email protected]
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ABSTRACT
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In the present study, two molecular complexes of 2,6-DHB with pharmaceutically active nutraceuticals i.e. nicotinic acid (NA) and nicotinamide (NIC) have been synthesized and preliminarily characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and FT-IR spectroscopy. Finally the crystal structures were solved by single crystal X-ray diffraction and the structures were analyzed in terms of supramolecular interactions. The salt 1 crystallizes in the monoclinic space group Cc, with a = 10.1503(1) Å, b = 12.3821(1) Å, c = 9.5291(1) Å, β = 94.343(1)°, V = 1194.20(2) Å3, Z = 4. The salt 2 crystallizes in monoclinic space group P21/n, with a = 7.0098 (1) Å, b = 12.5495 (1) Å, c = 13.4048 (1) Å, β = 92.746 (1)°, V = 1177.86 (2) Å3, Z = 4. The molecular packing of both salts are stabilized by N+−H···O–, O−H···O–, N−H···O and O−H···O hydrogen bonding interactions. DFT calculations substantiate the features of crystal structures. The Hirshfeld surfaces and the associated 2D fingerprint plots were investigated which revealed that more than two-third of close contacts were associated with relatively weak H···H, C···H and H···C interactions. The use of 3-D Hirshfeld surfaces in combination with 2-D fingerprint plots revealed that these weak interactions play major role in molecular crystal packing. Keywords: molecular salts, supramolecular hetero-synthon, 3-D Hirshfeld surface, 2-D fingerprint plots. 1. Introduction
Crystal engineering comprises an understanding of intermolecular interactions which govern the crystal packing, thus allowing the design of new solid forms with improved physical and chemical properties [1-5]. An organic crystal can be regarded as an ultimate supramolecule 1
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which is not only assembled via molecular recognition (supramolecular assembly) but also stabilized by weak, non-covalent interactions (crystal engineering). Salt formation is a widespread multicomponent approach to improve the physicochemical properties of the active pharmaceutical ingredients (APIs) in the pharmaceutical industry [8-10]. They have been shown
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to modulate the solubility and bioavailability of APIs [11-13]. Even hydrochloride salts of APIs can offer improved solubility and stability but hygroscopicity is a drawback of the product salts [14, 15]. A crystal engineering approach in selection of acid or base for a given API to make salts or co-crystals is reported in the literature [16-18]. Extensive research has been focused in
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the crystal engineering of systems having pyridine moieties i.e., nicotinic acid (NA), nicotinamide (NIC), isoniazid and isonicotinamide [19, 20] due to their broad spectrum of
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biological activities. NA is a potent lipid-modifying agent which decreases total cholesterol, LDL cholesterol, triglycerides and increase HDL cholesterol [21, 22]. NA is also reported to reduce coronary artery disease [23]. NIC is precursor to nicotinamide adenine dinucleotide phosphate (NADP), which is required for ATP synthesis, oxidation-reduction reactions, and ADP-ribose transfer reactions [24]. 2,6-DHB is strong acid because both hydroxyl groups form intramolecular hydrogen bonding with the carboxylic functionality [25]. This is reflected in the
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fact that both the molecular complexes of 2,6DHB exist as salts. The ∆pKa (∆pKa = pKa (base) pKa (acid)) criterion plays a major role in the acid-base reactions; if the ∆pKa is greater than 3 then salt formation is expected [26, 27]. Y. H. Luo et al. have reported the application of Hirshfeld surfaces analyses for the investigation intermolecular interactions of p-hydroxybenzoic
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acid [28].
In recent years, numerous techniques have been introduced to investigate the intermolecular
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interactions in crystal structures qualitatively and quantitatively, namely conformational similarity index for proteins [29] graph set analysis for hydrogen bonding [30], Hirshfeld surface analysis [31, 32] and so on. These methods are performed by specialised computer aided programs ESCET [33], COMPACK [34], Crystal Explorer [35] and dSNAP [36] respectively. The graphical tools based on Hirshfeld surface and the two dimensional (2D) fingerprint plots offer considerable promise for exploring packing patterns and intermolecular interactions in the molecular crystals [37].
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2,6-DHB - a versatile co-crystal former for APIs having N-heterocycles due to its hydroxyl and carboxyl functional groups, usually results in binary crystalline phases and robust supramolecular architectures. Thus an investigation of its supramolecular synthons pattern is of significant importance. Hence, the primary objective of the current study is the investigation of
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the supramolecular synthons of the two molecular slats of 2,6-DHB (scheme 1) for the purpose
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1
H
O
OH
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of understanding the influence of different N-heterocycles as co-crystal formers.
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O
2
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NH 2
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Scheme 1 Structure of molecular salts 1 and 2
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Hence in this work, we have studied the co-crystallization of 2,6-DHB with a series of Nheterocycles: nicotinic acid (NA), isonicotinic acid (INA), nicotinamide (NIC), isonicotinamide (IN) and 2-aminopyridine (2-AP) and we obtained two molecular salts 2,6-DHB−NA (1) and
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2,6-DHB−NIC (2). We characterized the structures of both molecular salts by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), single-crystal X-ray diffraction and FT-IR spectroscopy. The Hirshfeld surface and 2D fingerprint plot of 2,6-DHB in both the molecular salts were analyzed to investigate the influence of different N-heterocycles on the intermolecular interactions of the 2,6-DHB molecule. 2. Experimental 2.1. Materials 3
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All the starting materials i.e. 2,6-DHB (purity > 99.8%, CAS registry number: 303-07-1), NA (purity > 99.8%, CAS registry number: 59-67-6) and NIC (purity > 99.8%, CAS registry number: 98-92-0) were purchased from Sigma Aldrich (India) Ltd. Methanol with HPLC grade
2.2. Synthesis and growth of molecular salts 1 and 2
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purity was obtained from Molychem chemicals (India).
A 1:1 stoichiometric ratio of 2,6-DHB (50mg, 0.324 mmol) and NA (40mg, 0.324 mmol) were dissolved in methanol at 60° C for 10 minutes and the resulting homogeneous solution was kept undisturbed at ambient temperature for slow evaporation. Colorless block-shaped crystals of
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1 suitable for single crystal X-ray analysis were obtained after 2 days (yield 80%, based on 2,6DHB).
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The same procedure was followed for obtaining salt complex 2 by using NIC (40mg, 0.324 mmol) in lieu of NA. Colorless prism-shaped crystals of 2 were obtained after 3 days (yield 75%, based on 2,6-DHB). Various solvents like methanol, ethanol, acetonitrile, and acetone were tried for crystallization to obtain good quality of crystals. Among the four solvents used methanol was found to be the best solvent for growth of these crystals. 2.3. Powder X-ray Diffraction (PXRD)
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The PXRD patterns of all the samples were collected on a Bruker D8 Advance diffractometer (Germany) with 2.2 KW Cu anode, Ceramic X-ray tube source and Lynx Eye detector. The samples were scanned 4° and 80° in 2θ with a step size of 0.02°. 2.4. Differential scanning calorimetry (DSC)
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Thermal analyses of the starting components and the molecular salts 1 and 2 were performed on a differential scanning calorimeter (DSC 200 F3, Netzsch, Germany). The instrument was
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equipped with linear small compressor for cooling. The crystals (3-5 mg) were crimped in aluminium crucibles and scanned at a heating rate of 10°C/min in the range 30-250°C under dry nitrogen atmosphere (flow rate of 50 mL/min). The data were collected Proteus software version 5.2.1.
2.5. Infrared spectroscopy (FTIR) A Bruker Alpha-T Fourier transform infrared spectrophotometer was used record the IR spectra of the samples (sample concentration is 2 mg in 20 mg of KBr). The spectra were
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recorded over the spectral range 4000 to 600 cm−1 with resolution of 2 cm-1. Data were analyzed using OPUS software version 6.5. 2.6. Single crystal X-ray diffraction (SCXRD) Single-crystal X-ray diffraction data (Table 1) were collected at 183(2) K on an Agilent
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Technologies Super Nova Atlas area-detector diffractometer using a single wavelength Enhance X-ray source with Mo Kα radiation (λ = 0.71073 Å) [38] from a micro-focus X-ray source and an
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Oxford Instruments Cryojet XL cooler.
Table 1 Crystallographic data of the molecular salts 1 and 2 5
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The selected single crystals were mounted using polybutene oil on a flexible loop fixed on a goniometer head and immediately transferred to the diffractometer. Pre-experiment, data collection, data reduction and analytical absorption correction [39] were performed with the program suite CrysAlisPro [40]. The structure was solved by direct methods using SHELXS97
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[41]. The structure refinements were performed by full-matrix least-squares on F2 with SHELXL97 [41]. PLATON [42] was used to check the result of the X-ray analyses. All programs used during the crystal structure determination process are included in the WINGX software [43]. All the H positions bound to C atoms were calculated after each cycle of
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refinement using a riding model C−H = 0.93 Å and Uiso(H) = 1.2Ueq(C). All the H atoms bound to N and O atoms were located in difference Fourier maps and freely refined. The selected bond
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lengths and bond angles for compounds 1 & 2 are listed in Table 2, the relevant hydrogen bond
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parameters are provided in Table 3. In both the tables the ab-initio measurements are included.
Table 2 Selected bond lengths (Å) and angles (°) for 1 & 2
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Symmetry codes: (i) x+1/2, y+1/2, z+1 (ii) x, y+1, z (iii) x-1/2, -y-1/2, z-1/2
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2.7. Theoretical calculation
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Table 3 The hydrogen bonding geometrical parameters for 1 and 2
Molecular parameters as measured from XRD are very well supported by the DFT calculations carried out at B97D/6-311++G(d,p) level of theory. These are summarized in tables 2 and 3. Molecular Hirshfeld surfaces are generated by CrystalExplorer [35] computer program. Hirshfeld surface is an easily interpretable visualization of a molecule within its environment.
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The 2D fingerprint maps obtained from the reduced Hirshfeld surfaces provide the full distribution of intermolecular interactions. The principle of Hirshfeld surfaces are reported elsewhere [44-46]. 3. Results and discussion
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Salts can be distinguished from the co-crystals by the location of the proton between an acid and a base. The proton transfer can be evaluated from their SCXRD and FT-IR spectroscopic analyses. Salt formation was revealed from the single-crystal SCXRD analysis of the molecular
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salts 1 and 2 where the transferred hydrogen was located from a difference Fourier map [47]. 3.1. PXRD analysis
Powder X-ray diffraction is a fingerprint characterization technique for identification of new solid phases such as salts and co-crystals [48]. Both the multi-component salts display a unique crystalline PXRD patterns in comparison to the starting components (Fig. 1).
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Fig. 1 PXRD pattern of 2,6-DHB, 1 and 2
The powder X-ray diffraction of salt complex 1 exhibited characteristic reflections at about 2θ 14.22° and 28.68°. The salt complex 2 exhibited characteristic reflections at about 2θ 14.94°,
multicomponent solid forms. 3.2. Single crystal X-ray analysis
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16.42°, 19.21°, 26.55°, 27.68°, 29.02° and 39.76°, This indicates the formation of new
3.2.1. Description of the crystal structure of molecular salt 1(2,6-DHB–NA) The molecular salt 1 crystallizes as colorless block-shaped crystals. The structural
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determination shows 1 forms a 1:1 (2,6-DHB–NA) molecular salt in the monoclinic Cc space group with Z = 4, the asymmetric unit of 1 consists of one mono-protonated NA and one mono-
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anion of 2,6-DHB (Fig. 2).
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Fig. 2 Asymmetric unit of salt 1 showing atom-labeling scheme. In 1 the –COOH group of 2,6-DHB is ionized due to proton transfer to the pyridine nitrogen
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atom of the NA moiety while the –OH groups remain unionized. Proton transfer from the – COOH group (atom O3) to the pyridine ring (atom N1) is evidenced by the difference between the C–O bond distances C7–O3 = 1.273(8)Å, and C7–O4 = 1.267(9) Å of the carboxylate group with the ∆DC-O value of 0.006 Å. The relatively small ∆DC-O value which is expected for
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carboxylate group [49]. The protonation of NA on N1 site is reflected in the change in the bond angle. The angle at un-protonated ring N atom is 117.5° [50], while for protonated ring N atom the angle (C9-N1-C10) is 122.53(6)°. The torsion angles O1–C2–C3–C4 and O2–C6–C5–C4 are
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178.89(7)°, and 178.73(7) ° respectively. In this regard both the phenol groups are nearly in the same plane as the benzene ring of the anion. The torsion angle O5–C13–C8–C9 is 175.51(7)° indicates that the acid group is nearly in the same plane as pyridinium ring plane. In the crystal, the 2,6-DHB anion and pyridinium moiety of NA form a dimer unit by N1–H13···O3 and C10– H10···O4 hydrogen bonding interactions through R22(7) heterosynthon supramolecular ring
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bond interactions (Fig. 3).
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motif, the 2,6-DHB molecule also forms intramolecular O1–H1···O3 and O2–H2···O4 hydrogen
Fig.3 N+–H···O–, O–H···O and O–H···O– hydrogen bonding patterns in the basic supramolecular packing unit of 1 9
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The dimer unit then connects to two other units through O–H···O hydrogen bonding synthons, which involve –COOH and –OH functional groups. The overall crystal packing results
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in extended helical type supramolecular arrangement as shown in Fig. 4.
Fig. 4 The overall crystal packing of salt 1 resulting in helical type supramolecular architecture 3.2.2. Description of the crystal structure of molecular salt 2 (2,6-DHB–NIC)
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The molecular salt 2 crystallizes as colorless prism-shaped crystals. The structural determination shows 2 forms a 1:1 (2,6-DHB–NIC) molecular salt in the monoclinic P21/n space group with Z = 4, with the asymmetric unit consisting of one monocation of NIC and one
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monoanion of 2,6-DHB (Fig. 5).
Fig. 5 Asymmetric unit of salt 2, showing atom-labeling scheme. 10
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Proton transfer is evidenced by the difference between the C–O bond distances C7–O4 = 1.269(11) Å, and C7–O3 = 1.263(11) Å of the carboxylate group with the ∆DC-O value of 0.006 Å. The relatively small ∆DC-O value which is expected for carboxylate group [49].
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protonation of NIC on N1 site is reflected in the change in the bond angle. The angle at
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unprotonated ring N atom is 118.56(13)° [51], while for protonated ring N atom the angle (C9N1-C10) is 122.31(8)°. The torsion angles O1–C2–C3–C4 and O2–C6–C5–C4 are 179.68(9)°, and 176.85(9)°, respectively. In this regard both the phenol groups are nearly in the same plane as the benzene ring of the anion. The torsion angle O5–C13–C8–C12 is 167.98(9)° indicates that
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the amide group deviates by 12.02(9)° from the pyridinium ring plane. The crystal packing is mainly stabilized by N+–H···O– charge-assisted hydrogen bonds (N1–H6···O4 and N1–H6···O3)
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and also N–H···O neutral hydrogen bonding interactions (N2–H7···O2 and N2–H8···O1) (Fig.
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Fig. 6 N+–H···O–, N–H···O and O–H···O– hydrogen bonding patterns in the basic supramolecular packing unit of 2 The intramolecular charge-assisted O–H···O– hydrogen bonding interactions also stabilizing the molecular packing (O1–H1···O3 and O2–H2···O4). The deprotonation of 2,6-DHB leads to a boost of supramolecular synthons ability. The overall crystal packing resulted in the layered type of supramolecular architecture (Fig. 7).
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Fig. 7 The overall crystal packing of salt 2 resulting in layered type supramolecular arrangement 3.3. FT-IR spectral analysis
FT-IR spectroscopy is a widely used technique in the characterization of the formation of new solid phases and an excellent tool to distinguish the salts from co-crystals, especially when compounds having carboxylic acid group are used as a coformers [29]. The carbonyl (C=O) IR
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absorption frequency of carboxylic acid in 2,6-DHB observed at 1685 cm–1 which was absent in both the salts 1 and 2. Moreover the appearance of two characteristic carboxylate IR absorption vibrations at 1584 and 1345 cm–1 for 1 and 1587 and 1340 cm–1 for 2 due to asymmetric and symmetric O–C–O stretch respectively confirmed the proton transfer from the –COOH group in
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2,6-DHB [52]. The formations of salts are further supported by the appearance of strong bands at 1633 cm–1 for 1 and 1631 cm–1 for 2, which can be assigned to C=N vibrations characteristic of
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the quaternary nitrogen atom in a heterocyclic ring [53]. This strong C=N band due to strong ammono-aldehyde character of the pyridine ring, acquired as a result of quaternization was absent in both NA and NIC [54]. The FT-IR spectra of 2,6-DHB, 1 and 2 are shown in Fig. 8.
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Fig. 8 FT-IR spectra for 2,6-DHB, salt 1 and salt 2 3.4. Thermophysical properties
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in their DSC pattern (Fig. 9) .
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The two molecular complexes of 1 and 2 displayed an increased the thermal stability as in
Fig. 9 DSC thermograms showing the melting behavior of 2,6-DHB, 1 and 2
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The samples 2,6-DHB, 1 and 2 melted at 173.5°C, 186.5°C and 191.3°C with melting enthalpy of 90.94, 244.1 and 311.6 J/g respectively. The relation between enthalpy and melting
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temperature is shown in Fig. 10.
Fig. 10 Graph showing the relation between melting temperature and enthalpy of 2,6-DHB, 1 and 2
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The enthalpy of both the salts increased due to higher melting temperatures [55]. Therefore the salt formation increased both melting point and melting enthalpy. In case of 2,6-DHB, there is a noticeable degradation peak at 103.3 °C (∆H = 54.03 J/g) observed during heating, where as in case of molecular salts 1 and 2 no endothermic peaks related to similar degradation is
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observed. Both the salts are stable from 30 °C up to their corresponding melting temperature, which suggests the salts are anhydrous and homogeneous. Therefore the salts of 2,6-DHB of the
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present study demonstrated an increased level of thermal stability. 3.5. Hirshfeld surface analysis Each molecule in the asymmetric unit of a given crystal structure will have unique 3D Hirshfeld surface and 2D fingerprint map. Therefore a direct comparison can be made between 2,6-DHB molecules in different environments. Hirshfeld surfaces provide a three-dimensional picture of close contacts in a crystal, and these contacts can be summarized in a fingerprint map [56]. The distance from the Hirshfeld surface to the nearest atoms outside and inside the surface are characterized by the quantities de and di, respectively. The dnorm is a normalized contact 14
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distance based on de and di is defined as dnorm= (di - rivdW)/ rivdW + (de- revdW)/ revdW, symmetric in de and di with rivdW and revdW being the van der Waals radii of atoms. When dnorm is mapped on the Hirshfeld surface, close intermolecular distances are characterized by two identically colored regions, even if these occur on different molecules. The dnorm surface highlights both the donor
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and acceptor and it is therefore a versatile technique for analyzing the intermolecular interactions, such as hydrogen bonding interactions as well as weaker C–H···π interactions. The 3D Hirshfeld dnorm surfaces and 2D fingerprint maps of 2,6-DHB in molecular salts 1 and 2 are shown in Fig.11 and Fig.12 respectively, they clearly show the similarities and
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differences of the influences of the two different co-formers on the intermolecular interactions of
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the 2,6-DHB molecule.
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Fig. 11 3D dnorm surfaces of 2,6-DHB in molecular salts 1 (a) and 2 (b)
Fig. 12 2D fingerprint plots of 2,6-DHB in molecular salts 1 (a) and 2 (b)
The larger red circular regions on dnorm surfaces represent the strong hydrogen bonding interactions. The small red regions on the surfaces are corresponding to the C–H···π interactions. 15
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The pale yellow-green color points in the 2D fingerprint maps are corresponding to short contacts H···H, H···C and H···O interactions. For the molecular salt 1, N–H···O and O–H···O hydrogen bonding intermolecular interactions appear as two small spikes (upper left spike is sharp and lower right spike is broad) in the 2D fingerprint map, which have the most significant
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contribution to the total Hirshfeld surfaces of 1, comprised of 45.2%. The H–H interactions, which are appeared in the middle of scattered points in the 2D fingerprint map, comprises of 26.9% of the total Hirshfeld surfaces. The C–H···π interactions also have a relatively significant contribution to the total Hirshfeld surfaces of molecular salt 1, comprised of 9.4%, as was
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indicated by the “wings” in the upper left and lower right of the 2D fingerprint map. Apart from those above interactions, the presence of π···π (C–C), lone-pair···π (O–C) and lone-pair···lone-
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pair (O–O) interactions are observed and summarized in Table 4.
Table 4 Summary of the various contact contributions to the 2,6-DHB Hirshfeld surface area in molecular salts 1 and 2
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The Hirshfeld surfaces analysis for 2,6-DHB in molecular salt 2 is similar to 1. The N– H···O and O–H···O hydrogen bonding intermolecular interactions still have the most significant contribution to the total Hirshfeld surfaces of molecular salt 2, comprised of 40.4%, a little smaller than that in 1, then followed by H–H interactions (32%), little larger than that of
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molecular salt 1. The C–H···π interactions contribute 7.9% to the total Hirshfeld surfaces, a little smaller than that of molecular salt 1. The other contacts are summarized in Table 4.
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Salt formation in case of 2,6-DHB is not surprising as a CSD analysis revealed that almost all the multicomponent systems of 2,6-DHB, salt form is preferred. To explain why 2,6-DHB (pKa = 1.22) forms crystalline molecular salts with NA and NIC, we calculated ∆pKa values for both the salts 1 and 2 and other known crystal structures containing pyridine moieties and 2,6-DHB (Table 5). It has been observed that when the ∆pKa exceeds 2 (Table 5, Entries 2 & 4) salts were obtained.
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S.No.
Compound pKa
∆pKa Crystalline form
NA 4.85a 3.63 Salt* 1 NM 3.35a 2.13 Salt* 2 a PHZ 1.4 2,6-DHB0.22 Co-crystal57 PHZ 7 MEL 5.6a 8 2,6-DHB 4.38 Salt58 MEL a Obtained from Merck Index, *present study Table 5 ∆pKa values for complexes of 2,6-DHB
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1 2 3 4 5 6
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It has been reported in the literature that 2,6-DHB forms a co-crystal with phenazine [57] when the ∆pKa = 0.22, where as 2,6-DHB forms a salt with melamine [58] when ∆pKa = 4.38 (Table 5, Entries 6 & 8). 4. Conclusions
To summarize, we have reported synthesis, crystal growth, X-ray crystal structure analysis
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and the Hirshfeld surfaces analyses of two supramolecular complexes of 2,6-dihydroxybenzoic acid with nicotinic acid and nicotinamide respectively. The two salt complexes obtained by supramolecular synthons, mainly stabilized hydrogen bonding, H–H, C–H···π and lone-pair–π interactions. The analysis of 2D fingerprint maps revealed that N–H···O and O–H···O hydrogen
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bonding intermolecular interactions are more prominent in both the salts. The formation of complexes were further characterized and confirmed by FT-IR analysis. The crystal structures
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are stabilized by both charge-assisted N+−H···O–, O−H···O– as well as neutral N−H···O and O−H···O hydrogen bonding interactions. Formations of pyridinium ion and carboxylate anion were confirmed by FT-IR analysis. The molecular salts also displayed higher thermal stability compared to the starting materials. Acknowledgments KA thanks the management of Dayananda Sagar University for the financial Support and encouragement. VR would like to acknowledge SASTRA University for the computational infrastructure. 17
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Supporting Information Available Crystallographic data for the structural analysis have been deposited with Cambridge Crystallographic Data Center, CCDC Nos. 923884 for 1, and 923883 for 2. These data can be obtained
free
of
charge
from
the
Cambridge
Data
Centre
via
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www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic
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The paper reports the analysis of two salts of an N-heterocycle The salts have been characterized by various analytical techniques DFT calculations substantiates the crystal structure
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3-D Hirshfeld surfaces analysis in combination with 2-D fingerprint plots revealed that
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weak interactions play major role in molecular crystal packing.