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Salts of phenylacetic acid and 4-hydroxyphenylacetic acid with Cinchona alkaloids: Crystal structures, thermal analysis and FTIR spectroscopy
Journal of Molecular Structure 1114 (2016) 30e37
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Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc
Salts of phenylacetic acid and 4-hydroxyphenylacetic acid with Cinchona alkaloids: Crystal structures, thermal analysis and FTIR spectroscopy Francoise M. Amombo Noa, Ayesha Jacobs* Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, PO Box 652, Cape Town, 8000, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 November 2015 Received in revised form 3 February 2016 Accepted 3 February 2016 Available online 4 February 2016
Seven salts were formed with phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (HPAA) and the Cinchona alkaloids; cinchonidine (CIND), quinidine (QUID) and quinine (QUIN). For all the structures the proton was transferred from the carboxylic acid of the PAA/HPAA to the quinuclidine nitrogen of the respective Cinchona alkaloid. For six of the salts, water was included in the crystal structures with one of these also incorporating an isopropanol solvent molecule. However HPAA co-crystallised with quinine to form an anhydrous salt, (HPAA¡)(QUINþ). The thermal stability of the salts were determined and differential scanning calorimetry revealed that the (HPAA¡)(QUINþ) salt had the highest thermal stability compared to the other salt hydrates. The salts were also characterized using Fourier transform infrared spectroscopy. (PAA¡)(QUIDþ)·H2O and (PAA¡)(QUINþ)·H2O are isostructural and Hirshfeld surface analysis was completed to compare the intermolecular interactions in these two structures. © 2016 Elsevier B.V. All rights reserved.
Keywords: Cinchona alkaloids Phenylacetic acid 4-hydroxyphenylacetic acid Salt formation
1. Introduction The field of crystal engineering includes the design of novel materials via intermolecular interactions based on the supramolecular synthon approach [1,2]. Multicomponent complexes including co-crystals and salts have become a key resource in the basic concepts of supramolecular synthesis [3e9]. Hydrogen bonding is the driving force which often dominates in both cocrystal and salt formation [10,11]. Salts are differentiated from co-crystals by the location of the proton which is influenced by chemical and crystallographic factors and can be verified by single crystal X-ray diffraction experiments and spectroscopic data. The DpKa rule is based on the expectation that if the difference between the pKa of the base and the pKa of the acid is greater than 3 a salt is formed, whereas for DpKa < 0 a cocrystal is preferred. For DpKa between 0 and 3 it is difficult to predict the outcome of the co-crystallisation [12e14]. Zaworotko et al. [15] demonstrated that the synthesis of two components, 2aminopyridine and 4-aminobenzoic acid with a DpKa ¼ 2.07 resulted in salt formation. Other examples of the limitation of the DpKa rule are the structures of 2-aminopyridine with benzoic acid
* Corresponding author. E-mail address: [email protected] (A. Jacobs). http://dx.doi.org/10.1016/j.molstruc.2016.02.011 0022-2860/© 2016 Elsevier B.V. All rights reserved.
[16,17], and 4-aminobenzoic acid with 2-amino-4-methylpyridine [18]. The pKa rule has been validated by Cruz-Cabeza [19] using a dataset of 6465 acid-base complexes and the results showed that when DpKa > 4 a salt is formed and for DpKa < 1 a co-crystal is observed. For 1 < DpKa < 4 a correlation between DpKa and salt/ co-crystal formation has been established. In this work we report salt formations of phenylacetic acid (PAA) and 4-hydroxyphenylacetic acid (HPAA) with cinchonidine, quinidine and quinine. Attempted crystallization of cinchonine with both PAA and HPAA resulted in the recrystallization of cinchonine alone. Cinchona alkaloids are useful tools in the design of supramolecular structures as they are fairly large molecules that possess nitrogen atoms located in quinuclidine and quinoline rings as well as a hydroxyl group capable of hydrogen bonding. These compounds are natural products which are chiral and have been extensively employed in chiral resolutions of racemic mixtures. Helical supramolecular motifs consisting of Cinchona alkaloids and bile acids have also been reported [20]. The Cinchona alkaloids, in particular quinine are known anti-malarial drugs and are thus of pharmaceutical importance [21]. Salt/co-crystal formations of drugs are an important area of research as they can potentially improve the physicochemical properties of drug molecules. A recent review has highlighted the need for further research into the multicomponent crystal systems of anti-malarial drugs [22].
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Phenylacetic acid is a plant hormone [23]. PAA is also used in perfumes [24], in the biosynthesis of penicillin G [25] and its sodium salt is used in the treatment of hyperammonemia [26]. The crystal structure of PAA has been determined [27]. Inclusion compounds of PAA with organic molecules such as 2-pyridone [28], 3,30 -(hydrazine-1,2-diylidenedimethylylidene) dipyridine [29], 4,40 -(hydrazine-1,2-diylidenedimethylylidene) dipyridine [30], benzamide [31], adenine [32], 1-(carboxymethyl) pyridine [33], and hexamethylenetetramine [34] are also known. 4-Hydroxyphenylacetic acid is a phenolic acid found in olive oil [35]. The crystal structure of HPAA [36] as well as a co-crystal of HPAA with 4,4ʹ-bipyridine [37] have been reported. The chemical structures of PAA and HPAA with the salt formers are illustrated in Scheme 1.
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and crystals were obtained after one week. (HPAA¡)(QUIDþ)·H2O (6). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and quinidine (85.3 mg, 0.263 mmol) were dissolved in ethanol, and after 2 weeks crystals were obtained. Similar crystals were obtained using methanol, isopropanol and tetrahydrofuran as solvents. (HPAA¡)(QUINþ) (7). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and quinine (85.3 mg, 0.263 mmol) were dissolved in methanol. Crystals were obtained after 2 weeks. Similar crystals were obtained with ethanol, isopropanol and tetrahydrofuran as solvents. 2.2. Infrared (IR) spectroscopy
All chemicals were purchased from SigmaeAldrich and used as received.
Infrared spectra were acquired on a PerkineElmer FTIR 1000 spectrophotometer using KBr diffuse-reflectance mode (sample concentration 1 mg in 250 mg of KBr) for the collection of the IR spectra of the samples. Sample spectra were measured over the range of 4000-400 cm1 at a 2 cm1 spectral resolution.
2.1. Crystal growth
2.3. Powder X-ray diffraction
(PAA¡)(CINDþ)·H2O (1). Phenylacetic acid (40 mg, 0.294 mmol) and cinchonidine (86.6 mg, 0.294 mmol) were dissolved in isopropanol. The solution was allowed to evaporate and after 3 days crystals were obtained. (PAA¡)(QUIDþ)·H2O (2). Phenylacetic acid (40 mg, 0.294 mmol) and quinidine (95.4 mg, 0.294 mmol) were dissolved in acetone. Crystals were obtained after 3 days. Similar crystals were obtained using ethyl methyl ketone, tetrahydrofuran, isopropanol, ethanol and methanol as solvents. (PAA¡)(QUINþ)·H2O (3). Phenylacetic acid (40 mg, 0.294 mmol) and quinine (95.4 mg, 0.294 mmol) were dissolved in acetone. Crystals were obtained the same day. Similar crystals were obtained with ethyl methyl ketone, methanol, ethanol, isopropanol and tetrahydrofuran as solvents. (HPAA¡)(CINDþ)·½H2O (4). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and cinchonidine (77.4 mg, 0.263 mmol) were both dissolved in ethyl methyl ketone. Crystals were obtained after one week. (HPAA¡)(CINDþ)·IPA·H2O (5). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and cinchonidine (77.4 mg, 0.263 mmol) were dissolved in isopropanol (IPA). The solution was left to evaporate
The powder X-ray diffraction patterns of the samples were recorded with a D2 Phaser Bruker diffractometer with Cu-Ka radiation of 1.54184 Å. The samples were each scanned between 4 and 50 2q and the voltage tube and amperage were at 30 kV and 10 mA max, respectively with an Xflash detector and a scintillation counter, 1-dim LYNXEYE.
2. Experimental
O
O
OH
OH
2.4. Structure analysis Unit cell dimensions were determined from intensity data measured on a Bruker DUO APEX II [38] diffractometer using graphite-monochromated Mo-Ka radiation. The intensity data were collected by the standard phi scan and omega scan techniques scaled and reduced using SAINT-Plus [39]. Direct methods were used for all structures and the refinements were established by fullmatrix least squares with SHELX-97 [40]. X-seed [41] was used as a graphical interface. All non-hydrogen atoms in all structures were found in the difference electron density map and refined anisotropically. All of the hydrogens except the hydroxyl hydrogens and the hydrogen attached to the quinuclidine nitrogen were placed with geometric constraints and allowed to refine isotropically. The hydroxyl hydrogens and the hydrogens attached to the nitrogen were located in the difference electron density map and were either allowed to refine isotropically or distance restraints were applied. 2.5. Thermal analysis
HO
henylaceƟc acid (PAA)
Differential scanning calorimetry (DSC) and thermogravimetry (TG) were conducted for all the crystals on a PerkineElmer 6 system with a nitrogen purge of 20 ml min1. Experiments were performed from 303 to 600 K at a heating rate of 10 K min1. 3. Results and discussion
HO
HO
HO
3.1. Structures H3CO
H3CO
Cinchonidine
Quinidine
Quinine
(CIND)
(QUID)
(QUIN)
Scheme 1. Compounds used in this study.
The pKa1 values for quinine, quinidine and cinchonidine are 8.34, 8.77 and 8.40 respectfully [42]. In comparison the pKa value for PAA is 4.30 and that of HPAA is 4.57 [43]. Thus in all cases involving the acids and the selected Cinchona alkaloid, DpKa is close to 4 and the expectation is that salts will be formed. Although pKa values are usually obtained in aqueous media and is dependent on temperature and the solvent, DpKa is a useful tool to predict salt/
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F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
co-crystal formation [44,45]. Successful salt hydrates in the case of PAA with cinchonidine, quinine and quinidine were obtained. HPAA formed an anhydrous salt with quinine, a salt solvate and a salt hydrate with cinchonidine and a salt hydrate was observed with quinidine. Thus all of the crystal structures contained water except for the salt of HPAA and quinine. For all the structures the carboxylic acid proton was transferred to the quinuclidine nitrogen of the Cinchona alkaloid. Water is a small molecule and is known to incorporate into crystal structures, in some cases to provide additional hydrogen bonding sites if there is an imbalance in the number of hydrogen bond donors and acceptors between components [46]. PAA has the carboxylic acid functional group whereas the alkaloids (CIND/ QUIN/QUID) have the quinuclidine and quinoline nitrogens as well as the hydroxyl group which can participate in hydrogen bonding, the methoxy group is a weak acceptor. HPAA has the carboxylic acid functional group and the additional hydroxyl moiety in the para position. Thus there is an improved number of donor and acceptor groups between molecules in the case of HPAA and the alkaloids which could account in some part to the formation of the anhydrous (HPAA¡)(QUINþ). However HPAA formed salt hydrates with CIND and QUID. Studies have shown that in addition to the number of hydrogen bond donors and acceptors, the strength of the hydrogen bonds [47], size and branching of the solvent [48] also contribute towards the incorporation of solvent into crystal structures. The lattice energy also has to be considered [49,50] in solvate/hydrate formation. (PAA¡)(CINDþ)·H2O (1), was solved in the monoclinic space group C2 with Z ¼ 4. Both PAA¡ and CINDþ ions were found in general positions and the asymmetric unit contains one ion of each compound including a molecule of water (see Fig. 1(a)). The PAA¡ ring CeC distances were fixed due to disorder on the aromatic ring. Hydrogen bonding occurs between an oxygen on the PAA¡ and the protonated quinuclidine nitrogen found on the CINDþ cation (Nþ‒ H/¡OOC). The second oxygen atom on the PAA- is hydrogen bonded to the hydroxyl group of the CINDþ (OeH/¡OOC). Thus each PAA- ion is linked to two CINDþ cations to form C22 (9) chains [51]. A water molecule plays a bridging role between two PAA¡ ions, forming C22 (6) chains. The packing diagram of salt (1) is shown in Fig. 1 (b). The crystal structure is stabilized by weak CeH/p
interactions between CINDþ ions and between CINDþ and PAAions (see Table 1). There are also weak CH/N interactions (d(H/N) ¼ 2.784 Å, 2.909 Å) between the quinoline nitrogen of one CINDþ cation and CeH bonds on another CINDþ cation. The water molecules are located in isolated sites. The quinidinium salt hydrate, (PAA¡)(QUIDþ)·H2O (2), crystallized in P21 with Z ¼ 2. As was observed for structure (1), the water molecules are located in isolated sites. One of the oxygens in PAA¡ plays the role of a bifurcated acceptor connecting both the quinuclidinium nitrogen in QUIDþ and one of the water hydrogens. The OeH group of QUIDþ is hydrogen bonded to the second oxygen atom of the carboxylate PAA¡. Thus again each PAA- anion is linked to two QUIDþ cations to form C22 (9) chains. Unlike the CIND structure (1) the quinoline ring of the QUIDþ is connected to the water molecule via the nitrogen atom (see Fig. 2). There are also CeH/p interactions between QUIDþ ions and between QUIDþ and PAA¡ ions. The methoxy group of the QUIDþ cation is involved in weak CH/O interactions (d(HO) ¼ 2.480 Å) with the vinyl group of another QUIDþ ion. The hydrogen bonding in (PAA¡)(QUINþ)·H2O (3), is similar to that found in (PAA¡)(QUIDþ)·H2O (2) with similar crystal packing arrangements. Structure (3) also contains CeH/p interactions as for structure (2). Crystal data and their refinements for the salt hydrates obtained with PAA are given in Table 2. The addition of a hydroxyl group at the para position in PAA results in HPAA (4hydroxyphenylacetic acid). Table 3 tabulates the crystal data of the Cinchona alkaloid salts formed with HPAA. Structure (4), is the salt hemihydrate obtained between HPAA and CIND. (HPAA¡)(CINDþ)·½H2O was successfully solved in the monoclinic space group C2 with one ion of each component and half of a water molecule in the asymmetric unit. Both oxygen atoms on the carboxylate in HPAA¡ play a bifurcated acceptor role, because one of these oxygen atoms is linked to the protonated nitrogen atom of CINDþ and to the water hydrogen. The second oxygen atom forms a connection between the OeH of HPAA¡ and the OeH of CINDþ. As observed for the structures involving PAA, each HPAA¡ ion is linked to two CINDþ ions forming C22 (9) chains. In addition, the hydroxyl group of the HPAA¡ ions link neighbouring HPAA¡ ions and water molecules via C33 (15) chains. Hydrogen bonding and the crystal packing diagram along [010] of (4) are illustrated in Fig. 3(a) and (b). The quinoline nitrogen is involved in weak CH/N interactions with another CINDþ cation. The water molecules are located in isolated sites. Dissolution of a 1:1 M ratio of HPAA and CIND in isopropanol resulted in (HPAA¡)(CINDþ)·IPA·H2O (5), which was the only salt in the study with solvent molecules, besides water, included in the crystal structure. The structure was solved in P212121 with Z ¼ 4. The connectivity diagram of (HPAA¡)(CINDþ)·IPA·H2O is shown in Fig. 4 (a) in which the hydrogen bonds: (CINDþ) OH/¡OOC(HPAA¡), (H2O)OH/¡OOC(HPAA¡), (IPA)OH/O(H2O), (HPAA¡)OH/O(IPA) and (CIND)NþH/¡OOC(HPAA) are noted.
Table 1 CeH/p parameters of PAA structures. Compound
CeH/p
C/p (Å)
H/p (Å)
CeH-p ( )
1
C12eH12/p C15eH15/p C4BeH4B/p C20eH20B/p C27eH27A/p C14eH14/p C24eH24B/p
3.526 3.489 3.324 3.557 3.952 3.880 3.628
2.780 2.690 2.400 2.669 3.052 3.095 3.053
136 143 164 149 159 141 118
2 3 Fig. 1. (a) Hydrogen bonding in (1) and (b) Packing along [010] with water molecules shown in van der Waals radii.
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Fig. 2. (a) Hydrogen bonding in (2) and (b) Packing diagram along [100] with water molecules in van der Waals radii.
33
crystal packing diagrams of (6) are shown in Fig. 5(a) and (b). The methoxy group of the QUIDþ cation is involved in weak CH/O interactions (d(HO) ¼ 2.514 Å, 2.944 Å) with another QUIDþ ion. The water molecules occupy isolated sites. Interestingly 4-hydroxybenzoic acid formed a 2: 2 anhydrous salt with QUID [52] and demonstrated the Nþ‒H/OOC heterosynthon and two OeH/OOC synthons, with the quinoline nitrogen not involved in hydrogen bonding. Unlike the previous structures, where water or water/isopropanol was included in the crystal structures, dissolution of a 1:1 M ratio of HPAA: QUIN in methanol resulted in (HPAA)(QUINþ) (7). The structure was solved in the orthorhombic space group P212121 with one ion of each component in the asymmetric unit (Z ¼ 4). The hydrogen bonding in this structure is different to that found in the previous structures. One of the HPAA carboxylate oxygens is hydrogen bonded to QUINþ via its quinuclidinium nitrogen atom. The other carboxylate oxygen is linked to the OeH of another HPAA to form C11 (9) chains. In addition, QUINþ cations are linked via the OeH/N (quinoline) connection (see Fig. 6) to form C11 (7) chains. Again there are weak interactions between the methoxy group of QUINþ and the CH bonds of nearby QUINþ ions (d(HO) ¼ 2.905 Å, 2.957 Å). The hydrogen bond data for
Table 2 Crystallographic data and structure refinement parameters of PAA salts. Salt Code Structural formula Molecular mass (g mol1) Data collection Temp (K) Crystal size (mm) Space group a (Å) b (Å) c (Å) a ( ) b ( ) g ( ) Vol (Å3) Z Dc, calc density (g cm3) Absorption coeff (mm1) q range Reflections collected No data I >2 sigma (I) Final R indices [I >2 sigma (I)] R indices (all data) Goodness-of-fit on F2 CCDC no.
1
2
þ
(PAA )(CIND )·H2O þ (C8H7O 2 )(C19H23N2O )$H2O 448.55 173 (2) 0.09 0.18 0.45 C2 28.525 (6) 6.5303 (13) 15.172 (3) 90.00 120.24 (3) 90.00 2441.6 (11) 4 1.220 0.082 1.65e26.46 6192 3648 R1 ¼ 0.0543; wR2 ¼ 0.1287 R1 ¼ 0.0810; wR2 ¼ 0.1440 1.025 1435187
The two oxygen atoms of the carboxylate group also play a bifurcated acceptor role and form C22 (6) chains with water molecules and C22 (9) chains with CINDþ ions. In addition, one water molecule, two HPAA¡ anions and one CINDþ cation form a hydrogen bonded ring, R24 (11). The quinoline nitrogen is involved in weak CH/N interactions with another CINDþ cation. Unlike the previous structures, here the water and isopropanol molecules are located in channels (see Fig 4 (b)). (HPAA¡)(QUIDþ)·H2O (6) crystallised in the monoclinic space group P21 with Z ¼ 2. Both QUIDþ nitrogen atoms are involved in the hydrogen bonding. The protonated nitrogen is hydrogen bonded to one of the carboxylate oxygens in HPAA¡ and the neutral nitrogen is hydrogen bonded to the water molecule. Each water molecule is connected to a quinoline nitrogen atom of the QUIDþ cation, the hydroxyl group and the carboxylate group of the HPAA¡ anion. Again we note similar C22 (9) chains as seen previously. HPAA¡ ions and water molecules form C22 (11) chains. The hydrogen bonding and the
3
þ
(PAA )(QUID )·H2O þ (C8H7O 2 )(C20H25N2O2 )$H2O 478.57 173 (2) 0.06 0.08 0.10 P21 6.7225 (13) 19. 648 (4) 9.6505 (19) 90.00 99.45 (3) 90.00 1257.4 (4) 2 1.264 0.087 2.07e28.30 12662 5795 R1 ¼ 0.0336; wR2 ¼ 0.0847 R1 ¼ 0.0369; wR2 ¼ 0.0873 1.023 1435188
(PAA)(QUINþ)·H2O þ (C8H7O 2 )(C20H25N2O2 )$H2O 478.57 173 (2) 0.07 0.10 0.14 P21 6.5880 (13) 19.111 (4) 10.230 (2) 90.00 105.30 (3) 90.00 1242.3 (5) 2 1.279 0.088 2.06e28.33 13568 5603 R1 ¼ 0.0395; wR2 ¼ 0.1024 R1 ¼ 0.0445; wR2 ¼ 0.1064 1.028 1435189
all the structures is given in the supplementary information (Table 4). 3.2. Infrared spectroscopy Vibrational spectroscopic selection rules for the identification of salts and co-crystals is a continuous development, in particular Brittain studied 1: 1 co-crystal products of sodium salt formations of benzoic acid, phenylacetic acid, hydrocinnamic acid and 4phenylbutanoic acid [53]. This study found that the free acid absorption band occurs in the frequency range of 1680e1690 cm1. A salt is formed, when the free acid band disappears completely and is replaced by an anion band in the range of 1550e1600 cm1. However, the formation of a co-crystal is obtained when there is a small shift in the free acid absorption band towards higher energy (ranging from 1700 to 1730 cm1). The salt hydrate (1) as shown in Fig. 7 has IR absorption peaks of
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F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Table 3 Crystallographic data and structure refinement parameters of HPAA salts. Salt
4
5
6
7
Code Structural formula Molecular mass (g mol1) Data collection temp (K) Crystal size (mm) Space group a (Å) b (Å) c (Å) a ( ) b ( ) g ( ) Volume (Å3) Z Dc, calc density (g cm3) Absorption coefficient (mm1) q range Reflections collected No data I >2 sigma (I) Final R indices [I >2 sigma (I)] R indices (all data) Goodness-of-fit on F2 CCDC no.
(HPAA)(CINDþ)$½H2O þ (C8H7O 3 )(C19H23N2O )$H2O 455.54 173 (2) 0.05 0.06 0.56 C2 20.500 (4) 6.3585 (13) 19.061 (4) 90.00 111.60 (3) 90.00 2310.1 (9) 4 1.310 0.089 2.02e28.43 10825 4392 R1 ¼ 0.0453; wR2 ¼ 0.0949 R1 ¼ 0.0695; wR2 ¼ 0.1060 1.019 1435190
(HPAA)(CINDþ)$IPA$H2O þ (C8H7O 3 )(C19H23N2O )$C3H8O$H2O 524.64 173 (2) 0.05 0.11 0.43 P212121 6.6247 (13) 15.335 (3) 28.075 (6) 90.00 90.00 90.00 2852.1 (10) 4 1.222 0.085 1.45e28.34 29045 5643 R1 ¼ 0.0418; wR2 ¼ 0.0888 R1 ¼ 0.0612; wR2 ¼ 0.0973 1.012 1435191
(HPAA)(QUIDþ)$H2O þ (C8H7O 3 )(C20H25N2O2 )$H2O 494.57 173 (2) 0.07 0.20 0.45 P21 6.4974 (13) 19.303 (3) 10.263 (2) 90.00 105.29(3) 90.00 1241.6 (5) 2 1.323 0.093 2.11e28.28 12045 5743 R1 ¼ 0.0376; wR2 ¼ 0.0932 R1 ¼ 0.0409; wR2 ¼ 0.0954 1.045 1435192
(HPAA)(QUINþ) þ (C8H7O 3 )(C20H25N2O2 ) 476.56 173 (2) 0.07 0.20 0.45 P212121 8.4540 (17) 13.900 (3) 21.579 (4) 90.00 90.00 90.00 2535.8 (9) 4 1.248 0.086 1.74e26.40 5191 4397 R1 ¼ 0.0403; wR2 ¼ 0.0888 R1 ¼ 0.0532; wR2 ¼ 0.0952 1.057 1435193
band at 1384 cm1 which can be assigned to the CeO stretching mode. Structure (2) shows a new absorption band at 1587 cm1 which indicates the formation of a salt. The band at 3455 cm1 is attributed to the solvated water in (2) and the peak at 3210 cm1 to the NeH stretching vibration. (PAA¡)(QUINþ)·H2O (3) has both vibrational frequencies of PAA and QUIN. Similar to the (PAA¡)(QUIDþ)·H2O structure (2), salt (3) has a broad band at 1590 cm1 which is in the region of the C]O stretching mode for salt formation [53]. Other bands at 3206 cm1 and 3455 cm1 are observed and correspond to the NeH vibration and the water in the structure respectively. The hemihydrate salt (4) shows a new peak at 1640 cm1 attributed to n (CeO) of COO ‾ and a band at 3399 cm1 due to the OH group involved in hydrogen bonding. The salt solvate (5) shows a new band at 3142 cm1 which is attributed to the hydrogen bonded OH group and two new frequency vibrations at 1642 and 1613 cm1 indicating a proton transfer in the crystal structure. The appearance of a broad band at 3200 cm1 in compound (6) is assigned to the OH and NeH stretching modes. There is a new frequency vibration at 1584 cm1 confirming the formation of a salt according to Adalder et al. [54]. The salt (7) shows a broad absorption peak at 3451 cm1 which is due to the OH group involved in hydrogen bonding and an NeH stretch at 3085 cm1. The band at 1577 cm1 is attributed to the COO‾ group and the shift indicates a proton transfer. The IR spectra of the PAA and HPAA structures are given in the supporting information. 3.3. Thermal analysis
Fig. 3. Structure (4): (a) Hydrogen bonding and (b) Crystal packing along [010] with the water molecules in van der Waals radii.
both starting materials. There is a broad peak at 1570 cm1, which is within the range 1550e1650 cm1 indicating the transfer of a proton [53]. The frequency at 3509 cm1 can be attributed to the water molecule in the salt. The two bands at 3396 and 3126 cm1 are due to the hydrogen bonding of the OH. There is also a broad
The results of the DSC and TG analysis are summarized in Table 5 (See supporting information). The DSC of the salt hydrates and the salt solvate (5) gave two endothermic peaks, except for structures (2) and (6) that did not follow this decomposition pattern, viz loss of water/solvent followed by the melt of the salt. The DSC traces for (2) and (6) exhibit one endothermic peak at 374.7 K and 410.4 K respectively, which is due to simultaneous loss of water and the melt of the salt. Salt 7, gave rise to only one endothermic peak at 489.8 K which is the melt of the salt. This is the only salt with a melting point that is higher than that of the starting
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Fig. 4. (a) Packing diagram of (HPAA¡)(CINDþ)·IPA·H2O down [100] and (b) Channels in which water and isopropanol molecules are located down [100].
has a Ton ¼ 410.4 K compared to (PAA)(QUIDþ)·H2O, (2), (Ton ¼ 374.7 K). The water molecule in 6 is involved in three hydrogen bonds compared to the two hydrogen bonds for the water molecule in (2). The additional hydrogen bond in the crystal structure of (6) is due to the presence of the hydroxyl group on the HPAA. However such a correlation between the thermal stability of the salt hydrate and the number of hydrogen bonds involving the water molecules could not be found for the other salt hydrates. TG analyses of the salt hydrates/solvates are within 0.2e0.8% of the calculated % mass losses and correlates with the ratios found in the crystal structures. Thermal analysis curves of all the salts are given in the supporting information. 3.4. Neat grinding, liquid-assisted grinding and slurry experiments
Fig. 5. (HPAA¡)(QUIDþ)·H2O (6): (a) Hydrogen bonding and (b) Crystal packing diagram along [100] with water molecules in van der Waals radii.
Fig. 6. Packing diagram of (7) illustrating the hydrogen bonding.
materials, HPAA (m.p ¼ 425.1 K) and QUIN (m.p. ¼ 449.8 K) and it is also the most thermally stable salt compared to others in this study. In all cases the HPAA salts are more thermally stable than the corresponding PAA salt. For example (HPAA)(QUIDþ)·H2O, (6),
All neat grinding and liquid-assisted grinding experiments were conducted manually using a mortar and pestle. Slurry experiments were performed using 5e10 ml of solvent added to the known solid molar ratios with the resulting suspensions stirred at room temperature overnight. All powders were characterized using powder X-ray diffraction (PXRD). The results of each experiment are listed in Table 6 in the supporting information. Grinding and liquid-assisted grinding experiments for all the PAA salt hydrates were not possible due to the paste-like product obtained when PAA and the corresponding salt formers were ground together. The same situation happened when the physical mixture of these compounds was performed. Salts (1) and (3) could be prepared via slurry experiments in distilled water and there was good agreement between the slurry PXRD patterns and the calculated PXRD patterns obtained from LAZYPULVERIX [55]. The slurry experiment for salt (2) was conducted in isopropanol and its PXRD pattern matched the one from the crystal structure. Salts 4e7 could not be prepared using neat grinding; the PXRD patterns matched that of the physical mixture, thus indicating no reaction. Both liquid-assisted ground and slurry products obtained in distilled water were an excellent match with the calculated pattern (4) from LAZYPULVERIX. For compound (5), ground and physical mixture PXRD patterns were a match. However, the PXRD pattern of the slurry experiment performed in 50/50 (v/v) water/isopropanol did not correspond to either the physical mixture or the calculated pattern of salt (5) but was found to be similar to the calculated PXRD pattern of salt (4). In addition, drops of 50/50 (v/v) water/isopropanol were added to the
36
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Fig. 7. IR spectra of (a) PAA, (b) CIND and (c) (PAA¡)(CINDþ)·H2O.
ground product and the mixture was ground further for another 30 min. The pattern obtained did not match any other experiment conducted for this compound. Both neat grinding and slurry experiments of HPAA/QUID in ethanol did not give the physical mixture or the salt (6). This may be another form of the salt or the anhydrous salt (HPAA)(QUIDþ), but the crystallization of this form was unsuccessful. The same situation was found for HPAA/QUIN; each experiment was different from the others. The exact identity of this pattern is still unknown and may be a solvate of the salt or a different form of the salt. 3.5. Hirshfeld surface analysis Since the salt structures (2) and (3) are isostructural, Hirshfeld surfaces were used to compare the intermolecular interactions. This analysis was carried out in order to further understand the similarities and differences in the packing which stabilize these two compounds using CrystalExplorer [56e58]. 2D fingerprint plots were obtained for the two structures, each entity was identified as a QUIDþ/QUINþ cation and water molecules hydrogen bonded to the PAA anion. Fig. 8(a) and (b) show the 2D fingerprint plots for structures (2) and (3). The spikes labelled 1, 2, 3 and 4 are the contributions in percentage for O/H, C/H, H/H and N/H interactions found in both structures.
However, the N/H interactions (1.8%) in compound (3) are buried inside the fingerprint plot and are not visible as the N/H interactions (3.9%) of (2). These N/H interactions found in (2) are between the QUID and the water molecule, indicating that the water molecule is strongly held in the structure, which correlates with the DSC trace showing only one endotherm for both the loss of water and the salt melt. Both structures are strongly dominated by H/H interactions with 61.2% for compound (2) and 63.0% for (3). The C/H interactions which are attractive have a contribution percentage of 19.7% and 18.1% for (2) and (3) respectively. The O/H interactions for salt 3 are 15.5% which is slightly higher than that for salt (2) (13.8%). 4. Conclusion Both phenylacetic acid and 4-hydroxyphenylacetic acid successfully formed salts with quinine, quinidine and cinchonidine. In this study the crystal structures of seven salts were presented as well as their thermal stability and IR spectra. For all the structures the proton was transferred from the carboxylic acid to the quinuclidine nitrogen of the respective Cinchona alkaloid with the supramolecular heterosynthon Nþ‒H/OOC present in all of the structures. The hydroxyl group of the Cinchona alkaloids also plays a role in the hydrogen bonding forming OeH/OOC linkages. The
Fig. 8. 2D fingerprint plots of (a) (PAA¡)(QUIDþ)·H2O (2) and (b) (PAA¡)(QUINþ)·H2O (3) with spikes labelled 1e4 illustrating the O/H, C/H, H/H and N/H interactions respectively.
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
quinoline nitrogen is involved in OeH/N hydrogen bonds with water for the salt hydrates involving PAA with QUIN/QUID and HPAA with QUID. In the case of the anhydrous salt of HPAA with QUIN, the quinoline nitrogen forms (QUINþ)OeH/N hydrogen bonds. Six of the seven salts are hydrates with one of these also incorporating isopropanol in the crystal structure. The water molecules occupy isolated sites except for the salt solvate of HPAA and CIND where the water and isopropanol molecules are located in channels. Alternate methods of preparation of the salts were also investigated. The salt hydrates of phenylacetic acid were successfully prepared using the slurry method whereas only the cinchonidinium 4-hydroxyphenylacetate hemihydrate was obtained using liquid assisted grinding and the slurry method. 4-Hydroxyphenylacetic acid showed greater diversity in the stoichiometry of the obtained salts with a hemihydrate, solvate, monohydrate and an anhydrous salt compared to phenylacetic acid which gave salt monohydrates in all cases. Acknowledgements We thank the National Research Foundation (South Africa) and the Cape Peninsula University of Technology. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2016.02.011. References [1] G.R. Desiraju, Crystal Engineering: The Design of Organic Solids, Elsevier, Amsterdam, 1989. [2] G.R. Desiraju, Angew. Chem. Int. Ed. Engl. 34 (1995) 2311. € y, Acta Crystallogr. Sect. B 53 (1997) 569e586. [3] C.B. Aakero [4] T. Fris ci c, W. Jones, J. Pharm. Pharmacol. 62 (2010) 1547e1559. [5] P. Metrangolo, G. Resnati, Chem. Eur. J. 7 (2001) 2511e2519. [6] N. Shan, M.J. Zaworotko, Drug Discov. Today 13 (2008) 440e446. [7] A. Nangia, G.R. Desiraju, Top. Curr. Chem. 198 (1998) 58e95. [8] R. Thakuria, A. Delori, W. Jones, M.P. Lipert, L. Roy, N. Rodriguez-Hornedo, Int. J. Pharm. 453 (2013) 101e125. [9] K. Rissanen, CrystEngComm 10 (2008) 1107e1113. € y, J. Desper, M.E. Fasulo, CrystEngComm 8 (2006) 586e588. [10] C.B. Aakero [11] K. Biradha, CrystEngComm 5 (2003) 374e384. [12] B.R. Bhogala, S. Basavoju, A. Nangia, CrystEngComm 7 (2005) 551e562. [13] P.H. Stahl, C.G. Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use; International Union of Pure and Applied Chemistry, VHCA; Wiley-VCH, Weinheim, New York, 2002. [14] M. Smith, J. March, March's Advanced Organic Chemistry: Reaction, Mechanism, and Structure, fifth ed., John Wiley, New York, 2001. [15] J.A. Bis, M.J. Zaworotko, Cryst. Growth. Des. 5 (2005) 1169e1179. [16] M. Odabasoglu, O. Buyukgungor, P. Lonnecke, Acta Crystallogr. Sect. C. Cryst. Struct. Comm. 59 (2003) o51eo52. [17] D.H. He, Y.Y. Di, W.Y. Dan, Y.P. Liu, D.Q. Wang, Acta Chim. Slov. 57 (2010) 458.
37
[18] H. Shen, J.J. Nie, D.J. Xu, Acta Crystallogr. Sect. E Struct. Rep. Online. 64 (2008) o1129. [19] A.J. Cruz-Cabeza, CrystEngComm 14 (2012) 6362e6365. [20] T. Sasaki, N. Shizuki, I. Hiraishi, N. Tohnai, M. Miyata, Org. Biomol. Chem. 10 (2012) 5985e5992. [21] J. Achan, A.O. Talisuna, A. Erhart, A. Yeka, J.K. Tibenderana, F.N. Baliraine, P.J. Rosenthal, U. D'Alessandro, Malar. J. 10 (2011) 144. [22] M. Clements, T. le Roex, M. Blackie, Chem. Med. Chem. 10 (2015) 1786e1792. [23] F. Wightman, D.L. Lighly, Physiol. Plant. 55 (1982) 17e24. [24] K. Bauer, D. Garbe, H. Surburg, Common Fragrance and Flavor Materials: Preparation, Properties and Uses, John Wiley & Sons, 2008. [25] G. Lancini, F. Parenti, Antibiotics: an Integrated View, Springer Science & Business Media, 2013. [26] R.M. Kliegman, B. Stanton, J.St Geme, N.F. Schor, R.E. Behrman, Nelson Textbook of Pediatrics, Elsevier Health Sciences, 2015. [27] D.J. Hodgson, R.O. Asplund, Acta Crystallogr. Sect. C. Cryst. Struct. Comm. 47 (1991) 19. [28] T. Odani, A. Matsumoto, CrystEngComm 4 (2002) 467. [29] H.D. Arman, T. Kaulgud, E.R.T. Tiekink, Acta Crystallogr. Sect. E Struct. Rep. Online 66 (2010) o2684. [30] H.D. Arman, T. Kaulgud, E.R.T. Tiekink, Acta Crystallogr. Sect. E Struct. Rep. Online 66 (2010) o2629. [31] S.R. Chaudhari, N. Suryaprakash, J. Mol. Struct. 1016 (2012) 163. [32] B. Sridhar, K. Ravikumar, Acta Crystallogr. Sect. C. Cryst. Struct. Comm. 63 (2007) o415. [33] Z. Dega-Szafran, M. Jaskolski, M. Szafran, J. Mol. Struct. 555 (2000) 191. [34] T.C.W. Mak, C. Xiaoming, S. Kailiang, Y. Jiaxing, Z. Chaode, J. Crystallogr. Spectrosc. Res. 16 (1986) 639. [35] G. Paradopoulos, D. Boskou, J. Am. Oil. Chem. Soc. 68 (1991) 669. [36] S. Gracin, A. Fischer, Acta Crystallogr. Sect. E 61 (2005) o1919eo1920. [37] L. Jian-Feng, Z. Guo-Liang, Acta Crystallogr. Sect. E. Struct. Rep. Online 66 (2010) o1455. [38] APEX 2, Version 1.0-27, Bruker AXS Inc., Madison,Wisconsin, USA, 2005. [39] SAINT-Plus, Version 7.12, Bruker AXS Inc., Madison, Wisconsin, USA, 2004. [40] G.M. Sheldrick, SHELX-97, Program for Crystal Structure Refinement, Uni€ ttingen, Germany, 1997. versity of Go [41] L.J. Barbour, X-Seed e A Software Tool for Supramolecular Crystallography, J. Supramol. Chem. 1 (2001) 189e191. €hnrich, V. Tatar, Chromatographic Analysis of Alkaloids, Chro[42] M. Popl, J. Fa matographic Science, Marcel Dekker, New York, 1990. [43] T. Hanai, J. Chromatogr. Sci. 44 (2006) 247e252. [44] S.L. Childs, G.P. Stahly, A. Park, Mol. Pharm. 4 (2007) 323e338. [45] G. Ramon, K. Davies, L.R. Nassimbeni, CrystEngComm 16 (2014) 5802e5810. [46] A.L. Gillon, N. Feeder, R.J. Davey, R. Storey, Cryst. Growth. Des. 3 (2003) 663e673. [47] A. Nangia, G.R. Desiraju, Chem. Commun. (1999) 605e606. bia n, Cryst. Growth. Des. 16 (2016) 70e81. [48] K. Takieddin, Y.Z. Khimyak, L. Fa [49] D.E. Braun, P.G. Karamertzanis, S.L. Price, Chem. Commun. 47 (2011) 5443e5445. [50] A.J. Cruz-Cabeza, G. Day, W.D.S. Motherwell, W. Jones, J. Am. Chem. Soc. 128 (2006) 14466e14467. [51] M.C. Etter, J.C. MacDonald, J. Bernstein, Acta Crystallogr. B 46 (1990) 256e262. [52] M. Khan, V. Enkelmann, G. Brunklaus, CrystEngComm 13 (2011) 3213e3223. [53] H.G. Brittain, Cryst. Growth. Des. 10 (2010) 1990e2003. [54] T.K. Adalder, R. Sankali, P. Dastidar, Cryst. Growth. Des. 12 (2012) 2533e2542. [55] K. Yvon, W. Jeitschko, E. Parthe, J. Appl. Crystallogr. 10 (1977) 73e74. [56] M.A. Spackman, J.J. McKinnon, CrystEngComm 4 (2002), 978e392. [57] J.J. McKinnon, M.A. Spackman, A.S. Mitchell, Acta Crystallogr. B 60 (2004) 627e668. [58] J.J. McKinnon, D. Jayatilaka, M.A. Spackman, Chem. Commun. 37 (2007) 3814e3816.
Contents lists available at ScienceDirect
Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc
Salts of phenylacetic acid and 4-hydroxyphenylacetic acid with Cinchona alkaloids: Crystal structures, thermal analysis and FTIR spectroscopy Francoise M. Amombo Noa, Ayesha Jacobs* Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, PO Box 652, Cape Town, 8000, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 November 2015 Received in revised form 3 February 2016 Accepted 3 February 2016 Available online 4 February 2016
Seven salts were formed with phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (HPAA) and the Cinchona alkaloids; cinchonidine (CIND), quinidine (QUID) and quinine (QUIN). For all the structures the proton was transferred from the carboxylic acid of the PAA/HPAA to the quinuclidine nitrogen of the respective Cinchona alkaloid. For six of the salts, water was included in the crystal structures with one of these also incorporating an isopropanol solvent molecule. However HPAA co-crystallised with quinine to form an anhydrous salt, (HPAA¡)(QUINþ). The thermal stability of the salts were determined and differential scanning calorimetry revealed that the (HPAA¡)(QUINþ) salt had the highest thermal stability compared to the other salt hydrates. The salts were also characterized using Fourier transform infrared spectroscopy. (PAA¡)(QUIDþ)·H2O and (PAA¡)(QUINþ)·H2O are isostructural and Hirshfeld surface analysis was completed to compare the intermolecular interactions in these two structures. © 2016 Elsevier B.V. All rights reserved.
Keywords: Cinchona alkaloids Phenylacetic acid 4-hydroxyphenylacetic acid Salt formation
1. Introduction The field of crystal engineering includes the design of novel materials via intermolecular interactions based on the supramolecular synthon approach [1,2]. Multicomponent complexes including co-crystals and salts have become a key resource in the basic concepts of supramolecular synthesis [3e9]. Hydrogen bonding is the driving force which often dominates in both cocrystal and salt formation [10,11]. Salts are differentiated from co-crystals by the location of the proton which is influenced by chemical and crystallographic factors and can be verified by single crystal X-ray diffraction experiments and spectroscopic data. The DpKa rule is based on the expectation that if the difference between the pKa of the base and the pKa of the acid is greater than 3 a salt is formed, whereas for DpKa < 0 a cocrystal is preferred. For DpKa between 0 and 3 it is difficult to predict the outcome of the co-crystallisation [12e14]. Zaworotko et al. [15] demonstrated that the synthesis of two components, 2aminopyridine and 4-aminobenzoic acid with a DpKa ¼ 2.07 resulted in salt formation. Other examples of the limitation of the DpKa rule are the structures of 2-aminopyridine with benzoic acid
* Corresponding author. E-mail address: [email protected] (A. Jacobs). http://dx.doi.org/10.1016/j.molstruc.2016.02.011 0022-2860/© 2016 Elsevier B.V. All rights reserved.
[16,17], and 4-aminobenzoic acid with 2-amino-4-methylpyridine [18]. The pKa rule has been validated by Cruz-Cabeza [19] using a dataset of 6465 acid-base complexes and the results showed that when DpKa > 4 a salt is formed and for DpKa < 1 a co-crystal is observed. For 1 < DpKa < 4 a correlation between DpKa and salt/ co-crystal formation has been established. In this work we report salt formations of phenylacetic acid (PAA) and 4-hydroxyphenylacetic acid (HPAA) with cinchonidine, quinidine and quinine. Attempted crystallization of cinchonine with both PAA and HPAA resulted in the recrystallization of cinchonine alone. Cinchona alkaloids are useful tools in the design of supramolecular structures as they are fairly large molecules that possess nitrogen atoms located in quinuclidine and quinoline rings as well as a hydroxyl group capable of hydrogen bonding. These compounds are natural products which are chiral and have been extensively employed in chiral resolutions of racemic mixtures. Helical supramolecular motifs consisting of Cinchona alkaloids and bile acids have also been reported [20]. The Cinchona alkaloids, in particular quinine are known anti-malarial drugs and are thus of pharmaceutical importance [21]. Salt/co-crystal formations of drugs are an important area of research as they can potentially improve the physicochemical properties of drug molecules. A recent review has highlighted the need for further research into the multicomponent crystal systems of anti-malarial drugs [22].
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Phenylacetic acid is a plant hormone [23]. PAA is also used in perfumes [24], in the biosynthesis of penicillin G [25] and its sodium salt is used in the treatment of hyperammonemia [26]. The crystal structure of PAA has been determined [27]. Inclusion compounds of PAA with organic molecules such as 2-pyridone [28], 3,30 -(hydrazine-1,2-diylidenedimethylylidene) dipyridine [29], 4,40 -(hydrazine-1,2-diylidenedimethylylidene) dipyridine [30], benzamide [31], adenine [32], 1-(carboxymethyl) pyridine [33], and hexamethylenetetramine [34] are also known. 4-Hydroxyphenylacetic acid is a phenolic acid found in olive oil [35]. The crystal structure of HPAA [36] as well as a co-crystal of HPAA with 4,4ʹ-bipyridine [37] have been reported. The chemical structures of PAA and HPAA with the salt formers are illustrated in Scheme 1.
31
and crystals were obtained after one week. (HPAA¡)(QUIDþ)·H2O (6). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and quinidine (85.3 mg, 0.263 mmol) were dissolved in ethanol, and after 2 weeks crystals were obtained. Similar crystals were obtained using methanol, isopropanol and tetrahydrofuran as solvents. (HPAA¡)(QUINþ) (7). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and quinine (85.3 mg, 0.263 mmol) were dissolved in methanol. Crystals were obtained after 2 weeks. Similar crystals were obtained with ethanol, isopropanol and tetrahydrofuran as solvents. 2.2. Infrared (IR) spectroscopy
All chemicals were purchased from SigmaeAldrich and used as received.
Infrared spectra were acquired on a PerkineElmer FTIR 1000 spectrophotometer using KBr diffuse-reflectance mode (sample concentration 1 mg in 250 mg of KBr) for the collection of the IR spectra of the samples. Sample spectra were measured over the range of 4000-400 cm1 at a 2 cm1 spectral resolution.
2.1. Crystal growth
2.3. Powder X-ray diffraction
(PAA¡)(CINDþ)·H2O (1). Phenylacetic acid (40 mg, 0.294 mmol) and cinchonidine (86.6 mg, 0.294 mmol) were dissolved in isopropanol. The solution was allowed to evaporate and after 3 days crystals were obtained. (PAA¡)(QUIDþ)·H2O (2). Phenylacetic acid (40 mg, 0.294 mmol) and quinidine (95.4 mg, 0.294 mmol) were dissolved in acetone. Crystals were obtained after 3 days. Similar crystals were obtained using ethyl methyl ketone, tetrahydrofuran, isopropanol, ethanol and methanol as solvents. (PAA¡)(QUINþ)·H2O (3). Phenylacetic acid (40 mg, 0.294 mmol) and quinine (95.4 mg, 0.294 mmol) were dissolved in acetone. Crystals were obtained the same day. Similar crystals were obtained with ethyl methyl ketone, methanol, ethanol, isopropanol and tetrahydrofuran as solvents. (HPAA¡)(CINDþ)·½H2O (4). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and cinchonidine (77.4 mg, 0.263 mmol) were both dissolved in ethyl methyl ketone. Crystals were obtained after one week. (HPAA¡)(CINDþ)·IPA·H2O (5). 4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and cinchonidine (77.4 mg, 0.263 mmol) were dissolved in isopropanol (IPA). The solution was left to evaporate
The powder X-ray diffraction patterns of the samples were recorded with a D2 Phaser Bruker diffractometer with Cu-Ka radiation of 1.54184 Å. The samples were each scanned between 4 and 50 2q and the voltage tube and amperage were at 30 kV and 10 mA max, respectively with an Xflash detector and a scintillation counter, 1-dim LYNXEYE.
2. Experimental
O
O
OH
OH
2.4. Structure analysis Unit cell dimensions were determined from intensity data measured on a Bruker DUO APEX II [38] diffractometer using graphite-monochromated Mo-Ka radiation. The intensity data were collected by the standard phi scan and omega scan techniques scaled and reduced using SAINT-Plus [39]. Direct methods were used for all structures and the refinements were established by fullmatrix least squares with SHELX-97 [40]. X-seed [41] was used as a graphical interface. All non-hydrogen atoms in all structures were found in the difference electron density map and refined anisotropically. All of the hydrogens except the hydroxyl hydrogens and the hydrogen attached to the quinuclidine nitrogen were placed with geometric constraints and allowed to refine isotropically. The hydroxyl hydrogens and the hydrogens attached to the nitrogen were located in the difference electron density map and were either allowed to refine isotropically or distance restraints were applied. 2.5. Thermal analysis
HO
henylaceƟc acid (PAA)
Differential scanning calorimetry (DSC) and thermogravimetry (TG) were conducted for all the crystals on a PerkineElmer 6 system with a nitrogen purge of 20 ml min1. Experiments were performed from 303 to 600 K at a heating rate of 10 K min1. 3. Results and discussion
HO
HO
HO
3.1. Structures H3CO
H3CO
Cinchonidine
Quinidine
Quinine
(CIND)
(QUID)
(QUIN)
Scheme 1. Compounds used in this study.
The pKa1 values for quinine, quinidine and cinchonidine are 8.34, 8.77 and 8.40 respectfully [42]. In comparison the pKa value for PAA is 4.30 and that of HPAA is 4.57 [43]. Thus in all cases involving the acids and the selected Cinchona alkaloid, DpKa is close to 4 and the expectation is that salts will be formed. Although pKa values are usually obtained in aqueous media and is dependent on temperature and the solvent, DpKa is a useful tool to predict salt/
32
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
co-crystal formation [44,45]. Successful salt hydrates in the case of PAA with cinchonidine, quinine and quinidine were obtained. HPAA formed an anhydrous salt with quinine, a salt solvate and a salt hydrate with cinchonidine and a salt hydrate was observed with quinidine. Thus all of the crystal structures contained water except for the salt of HPAA and quinine. For all the structures the carboxylic acid proton was transferred to the quinuclidine nitrogen of the Cinchona alkaloid. Water is a small molecule and is known to incorporate into crystal structures, in some cases to provide additional hydrogen bonding sites if there is an imbalance in the number of hydrogen bond donors and acceptors between components [46]. PAA has the carboxylic acid functional group whereas the alkaloids (CIND/ QUIN/QUID) have the quinuclidine and quinoline nitrogens as well as the hydroxyl group which can participate in hydrogen bonding, the methoxy group is a weak acceptor. HPAA has the carboxylic acid functional group and the additional hydroxyl moiety in the para position. Thus there is an improved number of donor and acceptor groups between molecules in the case of HPAA and the alkaloids which could account in some part to the formation of the anhydrous (HPAA¡)(QUINþ). However HPAA formed salt hydrates with CIND and QUID. Studies have shown that in addition to the number of hydrogen bond donors and acceptors, the strength of the hydrogen bonds [47], size and branching of the solvent [48] also contribute towards the incorporation of solvent into crystal structures. The lattice energy also has to be considered [49,50] in solvate/hydrate formation. (PAA¡)(CINDþ)·H2O (1), was solved in the monoclinic space group C2 with Z ¼ 4. Both PAA¡ and CINDþ ions were found in general positions and the asymmetric unit contains one ion of each compound including a molecule of water (see Fig. 1(a)). The PAA¡ ring CeC distances were fixed due to disorder on the aromatic ring. Hydrogen bonding occurs between an oxygen on the PAA¡ and the protonated quinuclidine nitrogen found on the CINDþ cation (Nþ‒ H/¡OOC). The second oxygen atom on the PAA- is hydrogen bonded to the hydroxyl group of the CINDþ (OeH/¡OOC). Thus each PAA- ion is linked to two CINDþ cations to form C22 (9) chains [51]. A water molecule plays a bridging role between two PAA¡ ions, forming C22 (6) chains. The packing diagram of salt (1) is shown in Fig. 1 (b). The crystal structure is stabilized by weak CeH/p
interactions between CINDþ ions and between CINDþ and PAAions (see Table 1). There are also weak CH/N interactions (d(H/N) ¼ 2.784 Å, 2.909 Å) between the quinoline nitrogen of one CINDþ cation and CeH bonds on another CINDþ cation. The water molecules are located in isolated sites. The quinidinium salt hydrate, (PAA¡)(QUIDþ)·H2O (2), crystallized in P21 with Z ¼ 2. As was observed for structure (1), the water molecules are located in isolated sites. One of the oxygens in PAA¡ plays the role of a bifurcated acceptor connecting both the quinuclidinium nitrogen in QUIDþ and one of the water hydrogens. The OeH group of QUIDþ is hydrogen bonded to the second oxygen atom of the carboxylate PAA¡. Thus again each PAA- anion is linked to two QUIDþ cations to form C22 (9) chains. Unlike the CIND structure (1) the quinoline ring of the QUIDþ is connected to the water molecule via the nitrogen atom (see Fig. 2). There are also CeH/p interactions between QUIDþ ions and between QUIDþ and PAA¡ ions. The methoxy group of the QUIDþ cation is involved in weak CH/O interactions (d(HO) ¼ 2.480 Å) with the vinyl group of another QUIDþ ion. The hydrogen bonding in (PAA¡)(QUINþ)·H2O (3), is similar to that found in (PAA¡)(QUIDþ)·H2O (2) with similar crystal packing arrangements. Structure (3) also contains CeH/p interactions as for structure (2). Crystal data and their refinements for the salt hydrates obtained with PAA are given in Table 2. The addition of a hydroxyl group at the para position in PAA results in HPAA (4hydroxyphenylacetic acid). Table 3 tabulates the crystal data of the Cinchona alkaloid salts formed with HPAA. Structure (4), is the salt hemihydrate obtained between HPAA and CIND. (HPAA¡)(CINDþ)·½H2O was successfully solved in the monoclinic space group C2 with one ion of each component and half of a water molecule in the asymmetric unit. Both oxygen atoms on the carboxylate in HPAA¡ play a bifurcated acceptor role, because one of these oxygen atoms is linked to the protonated nitrogen atom of CINDþ and to the water hydrogen. The second oxygen atom forms a connection between the OeH of HPAA¡ and the OeH of CINDþ. As observed for the structures involving PAA, each HPAA¡ ion is linked to two CINDþ ions forming C22 (9) chains. In addition, the hydroxyl group of the HPAA¡ ions link neighbouring HPAA¡ ions and water molecules via C33 (15) chains. Hydrogen bonding and the crystal packing diagram along [010] of (4) are illustrated in Fig. 3(a) and (b). The quinoline nitrogen is involved in weak CH/N interactions with another CINDþ cation. The water molecules are located in isolated sites. Dissolution of a 1:1 M ratio of HPAA and CIND in isopropanol resulted in (HPAA¡)(CINDþ)·IPA·H2O (5), which was the only salt in the study with solvent molecules, besides water, included in the crystal structure. The structure was solved in P212121 with Z ¼ 4. The connectivity diagram of (HPAA¡)(CINDþ)·IPA·H2O is shown in Fig. 4 (a) in which the hydrogen bonds: (CINDþ) OH/¡OOC(HPAA¡), (H2O)OH/¡OOC(HPAA¡), (IPA)OH/O(H2O), (HPAA¡)OH/O(IPA) and (CIND)NþH/¡OOC(HPAA) are noted.
Table 1 CeH/p parameters of PAA structures. Compound
CeH/p
C/p (Å)
H/p (Å)
CeH-p ( )
1
C12eH12/p C15eH15/p C4BeH4B/p C20eH20B/p C27eH27A/p C14eH14/p C24eH24B/p
3.526 3.489 3.324 3.557 3.952 3.880 3.628
2.780 2.690 2.400 2.669 3.052 3.095 3.053
136 143 164 149 159 141 118
2 3 Fig. 1. (a) Hydrogen bonding in (1) and (b) Packing along [010] with water molecules shown in van der Waals radii.
F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Fig. 2. (a) Hydrogen bonding in (2) and (b) Packing diagram along [100] with water molecules in van der Waals radii.
33
crystal packing diagrams of (6) are shown in Fig. 5(a) and (b). The methoxy group of the QUIDþ cation is involved in weak CH/O interactions (d(HO) ¼ 2.514 Å, 2.944 Å) with another QUIDþ ion. The water molecules occupy isolated sites. Interestingly 4-hydroxybenzoic acid formed a 2: 2 anhydrous salt with QUID [52] and demonstrated the Nþ‒H/OOC heterosynthon and two OeH/OOC synthons, with the quinoline nitrogen not involved in hydrogen bonding. Unlike the previous structures, where water or water/isopropanol was included in the crystal structures, dissolution of a 1:1 M ratio of HPAA: QUIN in methanol resulted in (HPAA)(QUINþ) (7). The structure was solved in the orthorhombic space group P212121 with one ion of each component in the asymmetric unit (Z ¼ 4). The hydrogen bonding in this structure is different to that found in the previous structures. One of the HPAA carboxylate oxygens is hydrogen bonded to QUINþ via its quinuclidinium nitrogen atom. The other carboxylate oxygen is linked to the OeH of another HPAA to form C11 (9) chains. In addition, QUINþ cations are linked via the OeH/N (quinoline) connection (see Fig. 6) to form C11 (7) chains. Again there are weak interactions between the methoxy group of QUINþ and the CH bonds of nearby QUINþ ions (d(HO) ¼ 2.905 Å, 2.957 Å). The hydrogen bond data for
Table 2 Crystallographic data and structure refinement parameters of PAA salts. Salt Code Structural formula Molecular mass (g mol1) Data collection Temp (K) Crystal size (mm) Space group a (Å) b (Å) c (Å) a ( ) b ( ) g ( ) Vol (Å3) Z Dc, calc density (g cm3) Absorption coeff (mm1) q range Reflections collected No data I >2 sigma (I) Final R indices [I >2 sigma (I)] R indices (all data) Goodness-of-fit on F2 CCDC no.
1
2
þ
(PAA )(CIND )·H2O þ (C8H7O 2 )(C19H23N2O )$H2O 448.55 173 (2) 0.09 0.18 0.45 C2 28.525 (6) 6.5303 (13) 15.172 (3) 90.00 120.24 (3) 90.00 2441.6 (11) 4 1.220 0.082 1.65e26.46 6192 3648 R1 ¼ 0.0543; wR2 ¼ 0.1287 R1 ¼ 0.0810; wR2 ¼ 0.1440 1.025 1435187
The two oxygen atoms of the carboxylate group also play a bifurcated acceptor role and form C22 (6) chains with water molecules and C22 (9) chains with CINDþ ions. In addition, one water molecule, two HPAA¡ anions and one CINDþ cation form a hydrogen bonded ring, R24 (11). The quinoline nitrogen is involved in weak CH/N interactions with another CINDþ cation. Unlike the previous structures, here the water and isopropanol molecules are located in channels (see Fig 4 (b)). (HPAA¡)(QUIDþ)·H2O (6) crystallised in the monoclinic space group P21 with Z ¼ 2. Both QUIDþ nitrogen atoms are involved in the hydrogen bonding. The protonated nitrogen is hydrogen bonded to one of the carboxylate oxygens in HPAA¡ and the neutral nitrogen is hydrogen bonded to the water molecule. Each water molecule is connected to a quinoline nitrogen atom of the QUIDþ cation, the hydroxyl group and the carboxylate group of the HPAA¡ anion. Again we note similar C22 (9) chains as seen previously. HPAA¡ ions and water molecules form C22 (11) chains. The hydrogen bonding and the
3
þ
(PAA )(QUID )·H2O þ (C8H7O 2 )(C20H25N2O2 )$H2O 478.57 173 (2) 0.06 0.08 0.10 P21 6.7225 (13) 19. 648 (4) 9.6505 (19) 90.00 99.45 (3) 90.00 1257.4 (4) 2 1.264 0.087 2.07e28.30 12662 5795 R1 ¼ 0.0336; wR2 ¼ 0.0847 R1 ¼ 0.0369; wR2 ¼ 0.0873 1.023 1435188
(PAA)(QUINþ)·H2O þ (C8H7O 2 )(C20H25N2O2 )$H2O 478.57 173 (2) 0.07 0.10 0.14 P21 6.5880 (13) 19.111 (4) 10.230 (2) 90.00 105.30 (3) 90.00 1242.3 (5) 2 1.279 0.088 2.06e28.33 13568 5603 R1 ¼ 0.0395; wR2 ¼ 0.1024 R1 ¼ 0.0445; wR2 ¼ 0.1064 1.028 1435189
all the structures is given in the supplementary information (Table 4). 3.2. Infrared spectroscopy Vibrational spectroscopic selection rules for the identification of salts and co-crystals is a continuous development, in particular Brittain studied 1: 1 co-crystal products of sodium salt formations of benzoic acid, phenylacetic acid, hydrocinnamic acid and 4phenylbutanoic acid [53]. This study found that the free acid absorption band occurs in the frequency range of 1680e1690 cm1. A salt is formed, when the free acid band disappears completely and is replaced by an anion band in the range of 1550e1600 cm1. However, the formation of a co-crystal is obtained when there is a small shift in the free acid absorption band towards higher energy (ranging from 1700 to 1730 cm1). The salt hydrate (1) as shown in Fig. 7 has IR absorption peaks of
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Table 3 Crystallographic data and structure refinement parameters of HPAA salts. Salt
4
5
6
7
Code Structural formula Molecular mass (g mol1) Data collection temp (K) Crystal size (mm) Space group a (Å) b (Å) c (Å) a ( ) b ( ) g ( ) Volume (Å3) Z Dc, calc density (g cm3) Absorption coefficient (mm1) q range Reflections collected No data I >2 sigma (I) Final R indices [I >2 sigma (I)] R indices (all data) Goodness-of-fit on F2 CCDC no.
(HPAA)(CINDþ)$½H2O þ (C8H7O 3 )(C19H23N2O )$H2O 455.54 173 (2) 0.05 0.06 0.56 C2 20.500 (4) 6.3585 (13) 19.061 (4) 90.00 111.60 (3) 90.00 2310.1 (9) 4 1.310 0.089 2.02e28.43 10825 4392 R1 ¼ 0.0453; wR2 ¼ 0.0949 R1 ¼ 0.0695; wR2 ¼ 0.1060 1.019 1435190
(HPAA)(CINDþ)$IPA$H2O þ (C8H7O 3 )(C19H23N2O )$C3H8O$H2O 524.64 173 (2) 0.05 0.11 0.43 P212121 6.6247 (13) 15.335 (3) 28.075 (6) 90.00 90.00 90.00 2852.1 (10) 4 1.222 0.085 1.45e28.34 29045 5643 R1 ¼ 0.0418; wR2 ¼ 0.0888 R1 ¼ 0.0612; wR2 ¼ 0.0973 1.012 1435191
(HPAA)(QUIDþ)$H2O þ (C8H7O 3 )(C20H25N2O2 )$H2O 494.57 173 (2) 0.07 0.20 0.45 P21 6.4974 (13) 19.303 (3) 10.263 (2) 90.00 105.29(3) 90.00 1241.6 (5) 2 1.323 0.093 2.11e28.28 12045 5743 R1 ¼ 0.0376; wR2 ¼ 0.0932 R1 ¼ 0.0409; wR2 ¼ 0.0954 1.045 1435192
(HPAA)(QUINþ) þ (C8H7O 3 )(C20H25N2O2 ) 476.56 173 (2) 0.07 0.20 0.45 P212121 8.4540 (17) 13.900 (3) 21.579 (4) 90.00 90.00 90.00 2535.8 (9) 4 1.248 0.086 1.74e26.40 5191 4397 R1 ¼ 0.0403; wR2 ¼ 0.0888 R1 ¼ 0.0532; wR2 ¼ 0.0952 1.057 1435193
band at 1384 cm1 which can be assigned to the CeO stretching mode. Structure (2) shows a new absorption band at 1587 cm1 which indicates the formation of a salt. The band at 3455 cm1 is attributed to the solvated water in (2) and the peak at 3210 cm1 to the NeH stretching vibration. (PAA¡)(QUINþ)·H2O (3) has both vibrational frequencies of PAA and QUIN. Similar to the (PAA¡)(QUIDþ)·H2O structure (2), salt (3) has a broad band at 1590 cm1 which is in the region of the C]O stretching mode for salt formation [53]. Other bands at 3206 cm1 and 3455 cm1 are observed and correspond to the NeH vibration and the water in the structure respectively. The hemihydrate salt (4) shows a new peak at 1640 cm1 attributed to n (CeO) of COO ‾ and a band at 3399 cm1 due to the OH group involved in hydrogen bonding. The salt solvate (5) shows a new band at 3142 cm1 which is attributed to the hydrogen bonded OH group and two new frequency vibrations at 1642 and 1613 cm1 indicating a proton transfer in the crystal structure. The appearance of a broad band at 3200 cm1 in compound (6) is assigned to the OH and NeH stretching modes. There is a new frequency vibration at 1584 cm1 confirming the formation of a salt according to Adalder et al. [54]. The salt (7) shows a broad absorption peak at 3451 cm1 which is due to the OH group involved in hydrogen bonding and an NeH stretch at 3085 cm1. The band at 1577 cm1 is attributed to the COO‾ group and the shift indicates a proton transfer. The IR spectra of the PAA and HPAA structures are given in the supporting information. 3.3. Thermal analysis
Fig. 3. Structure (4): (a) Hydrogen bonding and (b) Crystal packing along [010] with the water molecules in van der Waals radii.
both starting materials. There is a broad peak at 1570 cm1, which is within the range 1550e1650 cm1 indicating the transfer of a proton [53]. The frequency at 3509 cm1 can be attributed to the water molecule in the salt. The two bands at 3396 and 3126 cm1 are due to the hydrogen bonding of the OH. There is also a broad
The results of the DSC and TG analysis are summarized in Table 5 (See supporting information). The DSC of the salt hydrates and the salt solvate (5) gave two endothermic peaks, except for structures (2) and (6) that did not follow this decomposition pattern, viz loss of water/solvent followed by the melt of the salt. The DSC traces for (2) and (6) exhibit one endothermic peak at 374.7 K and 410.4 K respectively, which is due to simultaneous loss of water and the melt of the salt. Salt 7, gave rise to only one endothermic peak at 489.8 K which is the melt of the salt. This is the only salt with a melting point that is higher than that of the starting
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35
Fig. 4. (a) Packing diagram of (HPAA¡)(CINDþ)·IPA·H2O down [100] and (b) Channels in which water and isopropanol molecules are located down [100].
has a Ton ¼ 410.4 K compared to (PAA)(QUIDþ)·H2O, (2), (Ton ¼ 374.7 K). The water molecule in 6 is involved in three hydrogen bonds compared to the two hydrogen bonds for the water molecule in (2). The additional hydrogen bond in the crystal structure of (6) is due to the presence of the hydroxyl group on the HPAA. However such a correlation between the thermal stability of the salt hydrate and the number of hydrogen bonds involving the water molecules could not be found for the other salt hydrates. TG analyses of the salt hydrates/solvates are within 0.2e0.8% of the calculated % mass losses and correlates with the ratios found in the crystal structures. Thermal analysis curves of all the salts are given in the supporting information. 3.4. Neat grinding, liquid-assisted grinding and slurry experiments
Fig. 5. (HPAA¡)(QUIDþ)·H2O (6): (a) Hydrogen bonding and (b) Crystal packing diagram along [100] with water molecules in van der Waals radii.
Fig. 6. Packing diagram of (7) illustrating the hydrogen bonding.
materials, HPAA (m.p ¼ 425.1 K) and QUIN (m.p. ¼ 449.8 K) and it is also the most thermally stable salt compared to others in this study. In all cases the HPAA salts are more thermally stable than the corresponding PAA salt. For example (HPAA)(QUIDþ)·H2O, (6),
All neat grinding and liquid-assisted grinding experiments were conducted manually using a mortar and pestle. Slurry experiments were performed using 5e10 ml of solvent added to the known solid molar ratios with the resulting suspensions stirred at room temperature overnight. All powders were characterized using powder X-ray diffraction (PXRD). The results of each experiment are listed in Table 6 in the supporting information. Grinding and liquid-assisted grinding experiments for all the PAA salt hydrates were not possible due to the paste-like product obtained when PAA and the corresponding salt formers were ground together. The same situation happened when the physical mixture of these compounds was performed. Salts (1) and (3) could be prepared via slurry experiments in distilled water and there was good agreement between the slurry PXRD patterns and the calculated PXRD patterns obtained from LAZYPULVERIX [55]. The slurry experiment for salt (2) was conducted in isopropanol and its PXRD pattern matched the one from the crystal structure. Salts 4e7 could not be prepared using neat grinding; the PXRD patterns matched that of the physical mixture, thus indicating no reaction. Both liquid-assisted ground and slurry products obtained in distilled water were an excellent match with the calculated pattern (4) from LAZYPULVERIX. For compound (5), ground and physical mixture PXRD patterns were a match. However, the PXRD pattern of the slurry experiment performed in 50/50 (v/v) water/isopropanol did not correspond to either the physical mixture or the calculated pattern of salt (5) but was found to be similar to the calculated PXRD pattern of salt (4). In addition, drops of 50/50 (v/v) water/isopropanol were added to the
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F.M. Amombo Noa, A. Jacobs / Journal of Molecular Structure 1114 (2016) 30e37
Fig. 7. IR spectra of (a) PAA, (b) CIND and (c) (PAA¡)(CINDþ)·H2O.
ground product and the mixture was ground further for another 30 min. The pattern obtained did not match any other experiment conducted for this compound. Both neat grinding and slurry experiments of HPAA/QUID in ethanol did not give the physical mixture or the salt (6). This may be another form of the salt or the anhydrous salt (HPAA)(QUIDþ), but the crystallization of this form was unsuccessful. The same situation was found for HPAA/QUIN; each experiment was different from the others. The exact identity of this pattern is still unknown and may be a solvate of the salt or a different form of the salt. 3.5. Hirshfeld surface analysis Since the salt structures (2) and (3) are isostructural, Hirshfeld surfaces were used to compare the intermolecular interactions. This analysis was carried out in order to further understand the similarities and differences in the packing which stabilize these two compounds using CrystalExplorer [56e58]. 2D fingerprint plots were obtained for the two structures, each entity was identified as a QUIDþ/QUINþ cation and water molecules hydrogen bonded to the PAA anion. Fig. 8(a) and (b) show the 2D fingerprint plots for structures (2) and (3). The spikes labelled 1, 2, 3 and 4 are the contributions in percentage for O/H, C/H, H/H and N/H interactions found in both structures.
However, the N/H interactions (1.8%) in compound (3) are buried inside the fingerprint plot and are not visible as the N/H interactions (3.9%) of (2). These N/H interactions found in (2) are between the QUID and the water molecule, indicating that the water molecule is strongly held in the structure, which correlates with the DSC trace showing only one endotherm for both the loss of water and the salt melt. Both structures are strongly dominated by H/H interactions with 61.2% for compound (2) and 63.0% for (3). The C/H interactions which are attractive have a contribution percentage of 19.7% and 18.1% for (2) and (3) respectively. The O/H interactions for salt 3 are 15.5% which is slightly higher than that for salt (2) (13.8%). 4. Conclusion Both phenylacetic acid and 4-hydroxyphenylacetic acid successfully formed salts with quinine, quinidine and cinchonidine. In this study the crystal structures of seven salts were presented as well as their thermal stability and IR spectra. For all the structures the proton was transferred from the carboxylic acid to the quinuclidine nitrogen of the respective Cinchona alkaloid with the supramolecular heterosynthon Nþ‒H/OOC present in all of the structures. The hydroxyl group of the Cinchona alkaloids also plays a role in the hydrogen bonding forming OeH/OOC linkages. The
Fig. 8. 2D fingerprint plots of (a) (PAA¡)(QUIDþ)·H2O (2) and (b) (PAA¡)(QUINþ)·H2O (3) with spikes labelled 1e4 illustrating the O/H, C/H, H/H and N/H interactions respectively.
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quinoline nitrogen is involved in OeH/N hydrogen bonds with water for the salt hydrates involving PAA with QUIN/QUID and HPAA with QUID. In the case of the anhydrous salt of HPAA with QUIN, the quinoline nitrogen forms (QUINþ)OeH/N hydrogen bonds. Six of the seven salts are hydrates with one of these also incorporating isopropanol in the crystal structure. The water molecules occupy isolated sites except for the salt solvate of HPAA and CIND where the water and isopropanol molecules are located in channels. Alternate methods of preparation of the salts were also investigated. The salt hydrates of phenylacetic acid were successfully prepared using the slurry method whereas only the cinchonidinium 4-hydroxyphenylacetate hemihydrate was obtained using liquid assisted grinding and the slurry method. 4-Hydroxyphenylacetic acid showed greater diversity in the stoichiometry of the obtained salts with a hemihydrate, solvate, monohydrate and an anhydrous salt compared to phenylacetic acid which gave salt monohydrates in all cases. Acknowledgements We thank the National Research Foundation (South Africa) and the Cape Peninsula University of Technology. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2016.02.011. References [1] G.R. Desiraju, Crystal Engineering: The Design of Organic Solids, Elsevier, Amsterdam, 1989. [2] G.R. Desiraju, Angew. Chem. Int. Ed. Engl. 34 (1995) 2311. € y, Acta Crystallogr. Sect. B 53 (1997) 569e586. [3] C.B. Aakero [4] T. Fris ci c, W. Jones, J. Pharm. Pharmacol. 62 (2010) 1547e1559. [5] P. Metrangolo, G. Resnati, Chem. Eur. J. 7 (2001) 2511e2519. [6] N. Shan, M.J. Zaworotko, Drug Discov. Today 13 (2008) 440e446. [7] A. Nangia, G.R. Desiraju, Top. Curr. Chem. 198 (1998) 58e95. [8] R. Thakuria, A. Delori, W. Jones, M.P. Lipert, L. Roy, N. Rodriguez-Hornedo, Int. J. Pharm. 453 (2013) 101e125. [9] K. Rissanen, CrystEngComm 10 (2008) 1107e1113. € y, J. Desper, M.E. Fasulo, CrystEngComm 8 (2006) 586e588. [10] C.B. Aakero [11] K. Biradha, CrystEngComm 5 (2003) 374e384. [12] B.R. Bhogala, S. Basavoju, A. Nangia, CrystEngComm 7 (2005) 551e562. [13] P.H. Stahl, C.G. Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use; International Union of Pure and Applied Chemistry, VHCA; Wiley-VCH, Weinheim, New York, 2002. [14] M. Smith, J. March, March's Advanced Organic Chemistry: Reaction, Mechanism, and Structure, fifth ed., John Wiley, New York, 2001. [15] J.A. Bis, M.J. Zaworotko, Cryst. Growth. Des. 5 (2005) 1169e1179. [16] M. Odabasoglu, O. Buyukgungor, P. Lonnecke, Acta Crystallogr. Sect. C. Cryst. Struct. Comm. 59 (2003) o51eo52. [17] D.H. He, Y.Y. Di, W.Y. Dan, Y.P. Liu, D.Q. Wang, Acta Chim. Slov. 57 (2010) 458.
37
[18] H. Shen, J.J. Nie, D.J. Xu, Acta Crystallogr. Sect. E Struct. Rep. Online. 64 (2008) o1129. [19] A.J. Cruz-Cabeza, CrystEngComm 14 (2012) 6362e6365. [20] T. Sasaki, N. Shizuki, I. Hiraishi, N. Tohnai, M. Miyata, Org. Biomol. Chem. 10 (2012) 5985e5992. [21] J. Achan, A.O. Talisuna, A. Erhart, A. Yeka, J.K. Tibenderana, F.N. Baliraine, P.J. Rosenthal, U. D'Alessandro, Malar. J. 10 (2011) 144. [22] M. Clements, T. le Roex, M. Blackie, Chem. Med. Chem. 10 (2015) 1786e1792. [23] F. Wightman, D.L. Lighly, Physiol. Plant. 55 (1982) 17e24. [24] K. Bauer, D. Garbe, H. Surburg, Common Fragrance and Flavor Materials: Preparation, Properties and Uses, John Wiley & Sons, 2008. [25] G. Lancini, F. Parenti, Antibiotics: an Integrated View, Springer Science & Business Media, 2013. [26] R.M. Kliegman, B. Stanton, J.St Geme, N.F. Schor, R.E. Behrman, Nelson Textbook of Pediatrics, Elsevier Health Sciences, 2015. [27] D.J. Hodgson, R.O. Asplund, Acta Crystallogr. Sect. C. Cryst. Struct. Comm. 47 (1991) 19. [28] T. Odani, A. Matsumoto, CrystEngComm 4 (2002) 467. [29] H.D. Arman, T. Kaulgud, E.R.T. Tiekink, Acta Crystallogr. Sect. E Struct. Rep. Online 66 (2010) o2684. [30] H.D. Arman, T. Kaulgud, E.R.T. Tiekink, Acta Crystallogr. Sect. E Struct. Rep. Online 66 (2010) o2629. [31] S.R. Chaudhari, N. Suryaprakash, J. Mol. Struct. 1016 (2012) 163. [32] B. Sridhar, K. Ravikumar, Acta Crystallogr. Sect. C. Cryst. Struct. Comm. 63 (2007) o415. [33] Z. Dega-Szafran, M. Jaskolski, M. Szafran, J. Mol. Struct. 555 (2000) 191. [34] T.C.W. Mak, C. Xiaoming, S. Kailiang, Y. Jiaxing, Z. Chaode, J. Crystallogr. Spectrosc. Res. 16 (1986) 639. [35] G. Paradopoulos, D. Boskou, J. Am. Oil. Chem. Soc. 68 (1991) 669. [36] S. Gracin, A. Fischer, Acta Crystallogr. Sect. E 61 (2005) o1919eo1920. [37] L. Jian-Feng, Z. Guo-Liang, Acta Crystallogr. Sect. E. Struct. Rep. Online 66 (2010) o1455. [38] APEX 2, Version 1.0-27, Bruker AXS Inc., Madison,Wisconsin, USA, 2005. [39] SAINT-Plus, Version 7.12, Bruker AXS Inc., Madison, Wisconsin, USA, 2004. [40] G.M. Sheldrick, SHELX-97, Program for Crystal Structure Refinement, Uni€ ttingen, Germany, 1997. versity of Go [41] L.J. Barbour, X-Seed e A Software Tool for Supramolecular Crystallography, J. Supramol. Chem. 1 (2001) 189e191. €hnrich, V. Tatar, Chromatographic Analysis of Alkaloids, Chro[42] M. Popl, J. Fa matographic Science, Marcel Dekker, New York, 1990. [43] T. Hanai, J. Chromatogr. Sci. 44 (2006) 247e252. [44] S.L. Childs, G.P. Stahly, A. Park, Mol. Pharm. 4 (2007) 323e338. [45] G. Ramon, K. Davies, L.R. Nassimbeni, CrystEngComm 16 (2014) 5802e5810. [46] A.L. Gillon, N. Feeder, R.J. Davey, R. Storey, Cryst. Growth. Des. 3 (2003) 663e673. [47] A. Nangia, G.R. Desiraju, Chem. Commun. (1999) 605e606. bia n, Cryst. Growth. Des. 16 (2016) 70e81. [48] K. Takieddin, Y.Z. Khimyak, L. Fa [49] D.E. Braun, P.G. Karamertzanis, S.L. Price, Chem. Commun. 47 (2011) 5443e5445. [50] A.J. Cruz-Cabeza, G. Day, W.D.S. Motherwell, W. Jones, J. Am. Chem. Soc. 128 (2006) 14466e14467. [51] M.C. Etter, J.C. MacDonald, J. Bernstein, Acta Crystallogr. B 46 (1990) 256e262. [52] M. Khan, V. Enkelmann, G. Brunklaus, CrystEngComm 13 (2011) 3213e3223. [53] H.G. Brittain, Cryst. Growth. Des. 10 (2010) 1990e2003. [54] T.K. Adalder, R. Sankali, P. Dastidar, Cryst. Growth. Des. 12 (2012) 2533e2542. [55] K. Yvon, W. Jeitschko, E. Parthe, J. Appl. Crystallogr. 10 (1977) 73e74. [56] M.A. Spackman, J.J. McKinnon, CrystEngComm 4 (2002), 978e392. [57] J.J. McKinnon, M.A. Spackman, A.S. Mitchell, Acta Crystallogr. B 60 (2004) 627e668. [58] J.J. McKinnon, D. Jayatilaka, M.A. Spackman, Chem. Commun. 37 (2007) 3814e3816.