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Article

Exploiting Supramolecular Synthons in Cocrystals of Two Racetams with 4-Hydroxybenzoic Acid and 4-Hydroxybenzamide Coformers

by
Jason Marquez
1,
Egor Novikov
1,
Sergei Rigin
1,2,
Marina S. Fonari
1,3,
Raúl Castañeda
1,
Tatiana Kornilova
1 and
Tatiana V. Timofeeva
1,*
1
Department of Chemistry, New Mexico Highlands University, Las Vegas, NM 87701, USA
2
Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27606, USA
3
Institute of Applied Physics, Moldova State University, Academiei Str. 5, MD2028 Chisinau, Moldova
*
Author to whom correspondence should be addressed.
Chemistry 2023, 5(2), 1089-1100; https://doi.org/10.3390/chemistry5020074
Submission received: 18 April 2023 / Revised: 3 May 2023 / Accepted: 4 May 2023 / Published: 8 May 2023
(This article belongs to the Section Crystallography)
Browse Figures
Versions Notes

Abstract

:
Structures of three cocrystals of nootropic racetams were studied. They included two cocrystals of phenylpiracetam (PPA) with 4-hydroxybenzoic acid (HBA) with different stoichiometries, PPA·HBA and PPA·2HBA, and cocrystal of 2-(4-phenyl-2-oxopyrrolidin-1-yl)-N’-isopropylideneacetohydrazide (PPAH) with 4-hydroxybenzamide (HBD), PPAH·HBD·(acetone solvate). X-ray study of the pure forms of PPA and PPAH was also carried out to identify variations of molecular synthons under the influence of conformers. The cocrystal structures revealed the diversity of supramolecular synthons namely, amide-amide, amide-acid, acid-acid, and hydroxyl-hydroxyl; however, very similar molecular chains were found in PPA and PPA·2HBA, and similar molecular dimers in PPAH and PPAH·HBD. In addition, conformational molecular diversity was observed as disorder in PPA·2HBA as it was observed earlier for rac-PPA that allows for the consideration that cocrystal as an example of partial solid solution. Quantum chemical calculations of PPA and PPAH conformers demonstrated that for most conformers, energy differences do not exceed 2 kcal/mol that suggests the influence of packing conditions (in this case R- and S-enantiomers intend to occupy the same molecular position in crystal) on molecular conformation.

Graphical Abstract

1. Introduction

Currently there is a significant interest in pharmaceutical materials that can be used for treatment of central nervous system (CNS) disorders. One of the groups of such materials is nootropics that are prescribed as drugs or supplements to improve memory, focus, and cognitive performance. Racetams (piracetam and its derivatives) are nootropic agents known since the 1970s [1,2,3,4]. Depending on their substituents, they have different degrees of pharmacological activity.
Nootropil (2-oxo-1-pyrrolidinyl-acetamide, piracetam, PA, Scheme 1) was marketed by the United Collection Bureau (UCB) to treat memory and balance problems [5]. The physiological action and structural peculiarities of PA have been studied thoroughly. This compound of one hydrate and five anhydrous crystalline forms was documented by Fabbiani et al. [6].
In search for nootropics with improved physicochemical properties, significant efforts were addressed to the PA cocrystals [7,8,9,10,11]. Zaworotko at al. [11] demonstrated the importance of supramolecular homo- and heterosynthons in crystal engineering of active pharmaceutical ingredients (APIs) for an explanation and prediction of polymorphic and cocrystalline forms of APIs. This paradigm looks significantly important for nonionized drugs like racetams since it depicts the relative ease with which pharmaceutical cocrystals can be prepared and diversified from the view point of their composition and physical properties. Several examples revealed the successful exploiting of carboxylic acid—primary amide supramolecular heterosynthon in crystal engineering of cocrystals including those that contain two APIs [12,13,14,15]. Among published examples of PA cocrystals containing two APIs, to mention a few, are carbamazepine with PA [8], 2,6-diaminopyridine with PA [9], myricetin with PA [16]. Viertelhaus et al. obtained six PA cocrystals with different organic acids [10]. Cocrystal screening through structural resemblance for eleven PA cocrystals with ten different acids was reported by Leyssens et al. [17]. Those examples demonstrated that the amide-carboxylic acid heterosynthon was rarely found in the crystal structures in the presence of additional hydrogen bond donors and acceptors. An example of significant change of properties by cocrystallization is PA—L-tartaric acid cocrystal. It was found that a reversible water adsorption with a maximum water uptake of 3% was observed for this cocrystal, while for pure PA it was more than 40% [10]. Such a drop of hygroscopicity is important for the pharmaceutical industry. An interesting peculiarity of PA-hydroquinone cocrystal [8] was that both coformers produced separate parallel 1D motifs of H-bonded PA and hydroquinone molecules. In paper [18] multi-component crystallization conditions of several APIs including PA allowed for obtaining new polymorph modifications and solvates of APIs.
Another member of racetams family, 2-(2-oxo-4-phenyl-1-pyrrolidinyl)acetamide (phenotropil, carphedon, phenylpiracetam, PPA, Scheme 1) demonstrates, apart from nootropic properties, strong antidepressant and anxiolytic activity [19]. The molecule of PPA contains one chiral center in the pyrrolidine ring. So, PPA exists in racemic and two enantiomeric, R- and S-forms (Scheme 1) [19,20]. Crystallographic data (CSD version 5.43, last update November 2022) are available for rac-PPA and polymorphs of R- and S-enantiomers [20,21]. Rac-PPA (refcodes QELNEB01, QELNEB) crystallizes in the triclinic P-1 space group. Stereoisomers crystallize as orthorhombic (refcode SAMZOY, P212121 space group) and triclinic (refcode SANBAN, P1 space group) polymorphs [19,20]. It should be mentioned that pharmacological activities of rac-PPA and its R- and S-enantiomers are different, and the memory-improving activity is only characteristic of R-enantiomer [22].
To mask their bitter taste, some racetams including PA and PPA were cocrystallized with saccharine and zinc saccharinate [7]. Particularly for PPA, these attempts resulted in preparation of two crystalline complexes, ZnSac2Car (Car = carphedon in [7], refcode NEFLOB) as a 1D coordination chain where both carbonyl oxygens of pyrrolidone and amide groups coordinate to two different zinc atoms, and [ZnSac2(H2O)2]·Car·EtOH·H2O (refcode NEFMOE) as a discrete inclusion compound with carphedon interacting with the [ZnSac2(H2O)2] complex through hydrogen bonding [7]. Apart from the PPA pure forms, these are the only two known examples of structurally studied multicomponent PPA crystals.
For 2-(4-phenyl-2-oxopyrrolidin-1-yl)-N’-isopropylideneacetohydrazide (PPAH, Scheme 1), a relatively new member of racetams family [19], to the best of our knowledge, no crystallographic information is available either for pure PPAH, or for its cocrystals.
The goal of this study was a search for new forms of nootropics PPA and PPAH, and a comparison of molecular synthons found in pure materials, different cocrystalline, and polymorphic forms. As coformers for PPA and PPAH, we used compounds with molecular structures similar to those which were successfully used for formation of PA cocrystals [10,11], such as 4-hydroxybenzoic acid (HBA) and 4-hydroxybenzamide (HBD). The HBA in particular has performed well in cocrystal design with APIs [11,23,24,25,26]. Structural, and computational studies were carried out for the following pure and cocrystalline materials: PPA, PPA·HBA, PPA·2HBA, PPAH, and PPAH·HBD·(acetone solvate).

2. Materials and Methods

2.1. Chemicals and Solvents

Phenylpiracetam powder (100%) was purchased from Purenootropics (Purenootropics.net), and Phenylpiracetam as a supplement in capsules was purchased from BrainMedics. 4-Hydroxybenzoic acid, 4-hydroxybenzamide, and acetone solvent were purchased from Sigma Aldrich and used without purification.

2.2. Synthesis

2.2.1. Synthesis of PPA·HBA (1:1) Cocrystal

An amount of 22.0 mg (0.1 mmol) of PPA and 14.0 mg (0.1 mmol) of HBA were dissolved in 5 mL of acetone at room temperature in a test tube covered with parafilm with a hole. After a week, the solvent had evaporated and crystals were observed.

2.2.2. Synthesis of PPA·2HBA (1:2) Cocrystal

An amount of 44.0 mg (0.2 mmol) of PPA and 42.0 mg (0.3 mmol) of HBA were dissolved in 5 mL of acetone at room temperature in a test tube covered with parafilm with a hole. After a week the solvent had evaporated and crystals were observed.

2.2.3. Synthesis of PPAH·HBD Cocrystal

Phenylpiracetam produced by BrainMedics was removed from capsules and used for cocrystallization. After cocrystal was obtained and characterized with single crystal X-ray diffraction analysis, we realized that instead of PPA we had its derivative, 2-(4-phenyl-2-oxopyrrolidin-1-yl)-N′-isopropylideneacetohydrazide (PPAH) presented in Scheme 1. To be sure that powder from capsules was indeed PPAH, we recrystallized it from acetone and the single crystal X-ray study unambiguously confirmed that the substance was PPAH not PPA. In addition, HPLC analysis was performed to check the purity of the substance from capsules. It demonstrated only one peak that stated the compound from capsules did not have any contaminations.

2.2.4. Synthesis of PPAH·HBD Cocrystal

To obtain the cocrystal, PPAH (27.0 mg, 0.1 mmol) and HBD (14.0 mg, 0.1 mmol) in 1:1 molar ratio were separately dissolved in 5 mL of acetone, filtered, and mixed. The resulting solution was covered with parafilm with small holes for slower evaporation and left at room temperature. Small colorless needles showed up on the vial walls after 24 h. Melting points for PPAH (144 °C), HBD (161 °C) and 1:1 cocrystal PPAH·HBD(acetone solvate) (108 °C) were measured on SRS MeltTemp apparatus. All samples were heated with a heat rate 1 °C/min until the substance was completely liquid.

2.3. Single-Crystal X-ray Diffraction Analysis

X-ray diffraction data for PPA, PPAH, and PPA·2HBA cocrystal, were collected on a SMART APEX II CCD diffractometer (Bruker AXS, Madison, WI [27] using graphite-monochromatized Mo Kα radiation (λ = 0.71073 Å). For PPA·HBA and PPAH·HBD cocrystals, X-ray diffraction data were collected on a Bruker D8 VENTURE diffractometer with microfocus sealed tube using graphite-monochromatized Cu Kα radiation (λ = 1.54178 Å). SADABS program was used for absorption correction and scaling of observed data [28]. The structures were solved by direct methods and refined by full-matrix least-squares on F2 for all data, using SHELXS97 [29] and OLEX 2.0 [30] software suites. The nonhydrogen atoms were refined in anisotropic approximation. The disorder was resolved for PPA in the pure form and in the 1:1 cocrystal PPA·HBA. The C–H atoms were fixed at idealized positions and refined with a riding-model approximation: C–H = 0.95–1.00 Å with Uiso(H) = 1.5 Ueq (C-methyl) and 1.2 Ueq (C) for other H atoms. The N–H and O–H hydrogens were located from the difference Fourier map or constrained. In cocrystal PPAH·HBD acetone solvent was disordered and the SQUEEZE procedure [31] was used to treat the diffused solvent in voids. The electron counts and the volume of associated voids indicated approximately one acetone solvent molecule per asymmetric unit. The sum formula reflected this ration. A check of the final CIF files (CCDC no.2247133-2247137) using PLATON did not show any missed symmetry. MERCURY2022.3.0 program (Cambridge Crystallographic Data Centre, Cambridge, UK)was used to make the molecular graphics [32].

2.4. Quantum Chemical Calculations

For the comparison of different enantiomers and their conformers quantum chemical calculations of total energy of PPA molecules in pure form (4 conformers), and in two cocrystals with HBA, PPAH in pure form and in cocrystal with HBD were carried out using GAUSSIAN 09 program package [33] and the B3LYP/6-311++G(d,p) level of theory [34]. The experimental X-ray coordinates were used for calculations. Correction on zero-point energy (ZPE) was included into molecular energy. A summary of results is presented in Table S1.

3. Results

Single crystal X-ray diffraction data, data collection, and structure refinement details are summarized in Table 1. Hydrogen bonding interactions were analyzed and finally calculated using the HTAB instruction in SHELXL [29], see Table 2.

3.1. Crystal Structures of PPA Pure Form, PPA·HBA and PPA·2HBA Cocrystals

Figure 1 reveals the contents of asymmetric units for PPA, PPA·HBA, and PPA·2HBA (the molecules with labelling schemes are summarized in Figure S1). To estimate if purchased PPA material represents a racemic mixture or enantiopure compound we carried out its diffraction study. It was found that this material was a racemate with two symmetrically independent molecular positions in the unit cell, each of which was occupied by either R- or S-enantiomers with almost equal ~50% occupation factor (Figure 1a). These results are very close to data previously published by Rekis et al. for rac-PPA [20]. The rac-PPA structure allowed the authors of the above mentioned paper to describe the molecular arrangement in this crystal as a solid solution of enantiomers. Such a situation is common for structures of enantiomers when R- and S-enantiomers are interchangeable due to their isosterism, or significant similarity of their molecular shapes [35,36,37,38,39]. It was also mentioned that conformational flexibility of enantiomers helps them to adjust to their positions in crystal lattice. For room-temperature crystal structure PPA·HBA, the disorder was not resolved during structure refinement (Figure 1b); however, thermal ellipsoids of the phenyl and pyrrolidone rings demonstrate hints of such disorder. For low-temperature structure PPA·2HBA the disorder model was found (Figure 1c) with occupancy factors of 0.510(6) and 0.490(6) for two disordered positions similar to the PPA pure form.
Cocrystals PPA·HBA and PPA·2HBA were grown using the different ratios of starting materials (1:1 and 2:3, see Experimental Section). It is worth mentioning that variable stoichiometric ratios are not uncommon for API cocrystals [11,40,41].
The PPA molecule in PPA, PPA·HBA, and PPA·2HBA crystals demonstrates conformational flexibility. Figure 2 presents three examples of overlay of the molecular structures of the same enantiomers found in the above mentioned crystals. Absolute and relative molecular energies of the enantiomers with different conformations are given in Table S1. It is possible to see that energy differences between these structures are not large and related mostly to different orientations of amide and phenyl groups attached to the oxopyrrolidine ring.
In the 1:1 cocrystal, PPA and HBA molecules are interlinked via amide-carboxylic acid supramolecular heterosynthon (N···O= 2.936(2) Å, O···O = 2.6329(17) Å, Table 2) and dimerize in the centrosymmetric tetramer (N···O = 2.9751(19) Å) via fusion of three cyclic motifs in the sequence R22(8)R42(8)R22(8) (Figure 3a) [42]. Such tetrameric motif was previously registered in the PA·HBA cocrystal and in some other cocrystals with HBA coformer [11,43,44]. The H-bonded tetramers are further interlinked via the hydroxyl group of HBA and carbonyl of PPA molecules (O···O 2.6638(18) Å), thus affording the H-bonded layer situated parallel to the bc plane. All H-bonds are concentrated within this layer. The layers stack along the crystallographic a-axis with interdigitating PPA phenyl rings (Figure 3b).
In the 1:2 cocrystal, PPA and HBA molecules are self-assembled in two separate homomeric H-bonded motifs that are interconnected. The PPA H-bonded chain is formed via alternation of two centrosymmetric supramolecular homosynthons, namely the typical amide-amide R22(8) homosynthon (N···O = 2.906(3) Å) and the less common larger R22(14) homosynthon (N···O = 2.999(3) Å) (Figure 4a). The similar infinitive H-bonded motif was registered for PA in the PA·HBA·H2O cocrystal [8] and for rac-PPA and S-PPA homomolecular forms (Figure 4b), except in the latter cases the amide-amide R22(8) homosynthons are non-centrosymmetric [20]. In the reported cocrystal, the PPA homomeric chains interdigitate forming the layer parallel to the (0 1-1) plane (Figure 4c) and stabilized by significantly less directional dispersion interactions (π(Ph)···π(Ph), CH(7)···π(Ph) = 2.1 Å) and weak C-H···O hydrogen bond (C···O = 3.42(2) Å). In turn, two chemically identical but crystallographically distinct HBA coformers are dimerized via robust R22(8) acid-acid supramolecular homosynthon (O···O = 2.671(2) Å and 2.599(2) Å) and form the tail-to-tail H-bonded chain via hydroxyl-groups (O···O = 2.636(2) Å) (Table 2). These carboxylic chains were also packed in the layers (Figure 4d). Similar to the 1:1 cocrystal, HBA and PPA interconnect through hydroxyl and carbonyl groups (O···O = 2.820(2) Å) that results in the 3D hydrogen bonded network where the homomeric PPA and HBA layers alternate (Figure S2). In addition to the already mentioned PA-hydroquinone cocrystal [8], PA and citric acid in cocrystal also form homomeric H-bonded domains that interconnect [10].

3.2. Crystal Structures of PPAH Pure Form and PPAH·HBD Cocrystal

Asymmetric units of PPAH and PPAH·HBD (the disordered acetone solvent molecule was excluded) crystals and overlapping diagram for PPAH from these two solids are shown in Figure 5a–c (for numbering see Figure S1). The geometrical parameters of the PPAH molecule are similar in the pure form and in the cocrystal. These similarities are evident from the overlay of these molecules presented in Figure 5c. Molecular energies of the PPAH molecule in pure crystal and in cocrystal are very close (Table S2).
PPAH crystallizes in the monoclinic P21/c space group with one molecule in the asymmetric unit. The expected dimerization of molecules occurs via amide-amide homosynthon, N···O = 2.948(2) Å (Figure 6a). The dimers pack in stacks along the shortest a-axis with only weak intermolecular CH···O interactions between stacks (Table 2, Figure 5b).
In the PPAH·HBD cocrystal, the self-association of each component occurs via amide-amide homosynthon (Figure 7a,b). Similar to the pure form, the PPAH molecules in cocrystal form the centrosymmetric dimers (N···O = 2.924(4) Å), while HBD coformers form the H-bonded double chain where the amide-amide homosynthons are further interlinked via synthon’s sequence …R22(8)R42(8)R22(8)… (N···O = 2.940(4), 3.064(4) Å, Table 2) identical with that found for (PPA)2(HBA)2 tetramers (Figure 2a). The discrete PPAH dimers and roughly planar HBD chains interconnect through HBD hydroxyl and PPAH carbonyl groups (O···O = 2.665(4) Å) resulting in the H-bonded layer (Figure 7c). An interesting feature is that the stacking pattern of PPAH in the pure form was conserved in cocrystal strengthening by the PPAH···HBD coformer H-bond (Figure S3). The packing of the layers remains voids of 241 Å3 filled by the disordered acetone solvent (Figure S4).
Quantum chemical calculations of PPA and PPAH conformers found in the pure materials and cocrystals (see Supplementary Materials) demonstrated that energy differences for most conformers do not exceed 2 kcal/mol. Such a difference suggests that conformational variations of these molecules are mostly defined by influence of packing conditions (in this case R- and S-enantiomers intend to occupy same molecular position in crystal) on molecular conformation.

4. Conclusions

Two cocrystals of phenylpiracetam (PPA) with 4-hydroxybenzylcarboxylic acid (HBA) coformer with different stoichiometry and a cocrystal of 2-(4-phenyl-2-oxopyrrolidin-1-yl)-N′-isopropylideneacetohydrazide (PPAH) with 4-hydroxybenzamide (HBD) coformer were obtained by cocrystallization experiments. Despite the fact that both racetams contain a primary amide as a main functional group for hydrogen bonding, the structures of reported cocrystals are significantly different and dependent on the interplay of amide-amide, amide-carboxylic acid, carboxylic acid-carboxylic acid supramolecular homo- and heterosynthons. Otherwise, the hydroxyl–carbonyl heterosynthon was found in all three cocrystal structures with both coformers. The H-bonded homomeric chain found in the PPA rac- and enantiopure forms, was also present in the 1:2 cocrystal resulting in alternation of PPA and HBA homomeric regions. The dimerization of PPAH via amide-amide supramolecular homosynthon led to the identical stacking of this homodimer as a dominating motif both in the cocrystal and in the racetam pure form. PPA in two cocrystals, PPA·HBA and PPA·2HBA demonstrated conformational freedom originating from the lack of strong intermolecular interactions with participation of phenyl and oxopyrrolidine rings that was reflected in disorder registered for these moieties in the crystals. The described situation allowed us to consider these cocrystals as examples of partial solid solutions.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry5020074/s1, Figure S1. ORTEP drawings with labelling schemes; Figure S2. Alternation of homomeric PPA and HBA H-bonded layers in cocrystal PPA·2HBA; Figure S3. Similar packing motifs in PPAH and PPAH·HBD cocrystal; Figure S4. Packing of PPAH·HBD H-bonded layers with voids filled by the disordered acetone solvent molecules; Table S1. Relative energies of PPA enantiomers with different conformations according to DFT calculations on B3LYP/6-311++(d,p) level of theory, kcal/mol; Table S2. Relative energies of PPAH enantiomers with different conformations according to DFT calculations on B3LYP/6-311++(d,p) level of theory, kcal/mol.

Author Contributions

Conceptualization, J.M. and T.V.T.; methodology, M.S.F.; investigation, J.M., E.N., S.R., M.S.F., R.C., T.K. and T.V.T.; writing—original draft preparation, M.S.F. and T.V.T.; writing—review and editing, all authors; visualization, M.S.F., E.N. and S.R.; supervision, T.V.T.; project administration, T.V.T. and M.S.F.; funding acquisition, T.V.T. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by NSF DMR PREM grants #1523611 and #2122108. M.S.F. thanks the project ANCD 20.80009.5007.15 for support.

Data Availability Statement

Any details are available from the authors. CCDC 2247133-2247137 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, accessed on 8 March 2023, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Acknowledgments

We thank Arkady Ellern for the help with data collection and structure solution of two presented crystalline materials.

Conflicts of Interest

The authors declare no conflict of interest.

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Chemistry 05 00074 sch001 550
Scheme 1. Structural formulas of piracetam (PA), S-phenylpiracetam (S-PPA), 2-(4-phenyl-2-oxopyrrolidin-1-yl)-N′-isopropylideneacetohydrazide (PPAH), and coformers 4-hydroxybenzoic acid (HBA) and 4-hydroxybenzamide (HBD).
Scheme 1. Structural formulas of piracetam (PA), S-phenylpiracetam (S-PPA), 2-(4-phenyl-2-oxopyrrolidin-1-yl)-N′-isopropylideneacetohydrazide (PPAH), and coformers 4-hydroxybenzoic acid (HBA) and 4-hydroxybenzamide (HBD).
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Figure 1. Contents of asymmetric units in: (a) PPA pure form, (b) PPA·HBA, and (c) PPA·2HBA cocrystals. Two disordered positions in PPA molecules are shown in Figure (a,c). Colorings scheme: oxygen—red; nitrogen—blue; carbon—grey; hydrogen—white, as used here and further.
Figure 1. Contents of asymmetric units in: (a) PPA pure form, (b) PPA·HBA, and (c) PPA·2HBA cocrystals. Two disordered positions in PPA molecules are shown in Figure (a,c). Colorings scheme: oxygen—red; nitrogen—blue; carbon—grey; hydrogen—white, as used here and further.
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Figure 2. Selected examples of comparison of PPA molecular structure in crystals of PPA·HBA, and PPA·2HBA: (a) Overlay of R-enantiomers of PPA from PPA·2HBA (green) and from PPA·HBA (red); (b) Overlay of S-enantiomer of PPA from PPA·2HBA (green) and from PPA·HBA (red); (c) Overlay of S-enantiomer of PPA from PPA·HBA (green) and from PPA·2HBA (red).
Figure 2. Selected examples of comparison of PPA molecular structure in crystals of PPA·HBA, and PPA·2HBA: (a) Overlay of R-enantiomers of PPA from PPA·2HBA (green) and from PPA·HBA (red); (b) Overlay of S-enantiomer of PPA from PPA·2HBA (green) and from PPA·HBA (red); (c) Overlay of S-enantiomer of PPA from PPA·HBA (green) and from PPA·2HBA (red).
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Figure 3. 1:1 cocrystal PPA·HBA: (a) View of (PPA)2(HBA)2 H-bonded tetramer. (b) Packing of two H-bonded layers in the crystal, view along the b-axis.
Figure 3. 1:1 cocrystal PPA·HBA: (a) View of (PPA)2(HBA)2 H-bonded tetramer. (b) Packing of two H-bonded layers in the crystal, view along the b-axis.
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Figure 4. Comparison of molecular synthons in rac-PPA and 1:2 cocrystal PPA·2HBA: (a) View of the PPA homomeric chain in PPA·2HBA; (b) PPA homomeric chain in rac-PPA; (c) Packing of PPA chains in the layer in cocrystal via CH···O short contacts and π-π stacking interactions between the phenyl rings. (d) Packing of HBA chains in stacking layer.
Figure 4. Comparison of molecular synthons in rac-PPA and 1:2 cocrystal PPA·2HBA: (a) View of the PPA homomeric chain in PPA·2HBA; (b) PPA homomeric chain in rac-PPA; (c) Packing of PPA chains in the layer in cocrystal via CH···O short contacts and π-π stacking interactions between the phenyl rings. (d) Packing of HBA chains in stacking layer.
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Figure 5. Content of asymmetric units in: (a) PPAH, (b) PPAH·HBD (see Supplementary Materials for structures with labels), and (c) overlay diagram for PPAH from pure material (green) and from cocrystal with HBD (red).
Figure 5. Content of asymmetric units in: (a) PPAH, (b) PPAH·HBD (see Supplementary Materials for structures with labels), and (c) overlay diagram for PPAH from pure material (green) and from cocrystal with HBD (red).
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Figure 6. (a) View of centrosymmetric dimer in PPAH, (b) packing of PPAH dimers in crystal, view along the a-axis.
Figure 6. (a) View of centrosymmetric dimer in PPAH, (b) packing of PPAH dimers in crystal, view along the a-axis.
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Figure 7. Cocrystal PPAH·HBD: (a) View of PPAH dimerization via amide-amide homosynthon with two HBD coformers attached to dimer via OH···O hydrogen bonds; (b) H-bonded double chain of HBD coformers; (c) Fragment of PPAH·HBD H-bonded layer, view along the b-axis.
Figure 7. Cocrystal PPAH·HBD: (a) View of PPAH dimerization via amide-amide homosynthon with two HBD coformers attached to dimer via OH···O hydrogen bonds; (b) H-bonded double chain of HBD coformers; (c) Fragment of PPAH·HBD H-bonded layer, view along the b-axis.
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Table
Table 1. Crystal data for pure forms PPA and PPAH and cocrystals PPA·HBA, PPA·2HBA, and PPAH·HBD·(acetone solvate).
Table 1. Crystal data for pure forms PPA and PPAH and cocrystals PPA·HBA, PPA·2HBA, and PPAH·HBD·(acetone solvate).
CompoundPPAPPA·HBAPPA·2HBAPPAHPPAH·HBD a
CCDC number22471352247137224713422471332247136
Empirical formulaC12H14N2O2C19H20N2O5C26H26N2O8C15H19N3O2C25H32N4O5
Formula weight218.25356.37494.49273.337468.54
Temperature/K150(2)293(2)150(2)100(2)173(2)
Crystal systemtriclinicmonoclinictriclinicmonoclinictriclinic
Space groupP-1P21/cP-1P21/cP-1
a/Å6.0917(17)18.9326(3)7.9851(8)5.5613(8)5.2285(3)
b/Å10.782(3)5.58410(10)12.6900(12)14.190(2)13.2516(7)
c/Å17.502(5)18.7881(4)13.6456(13)18.170(3)18.4515(9)
α/°76.700(4)90107.579(3)90104.612(4)
β/°85.742(5)118.9220(10)104.040(3)91.034(5)92.217(3)
γ/°81.827(5)90107.749(3)9092.539(3)
Volume/Å31106.3(5)1738.57(6)1167.0(2)1433.7(4)1234.22(12)
Z44242
ρcalc g/cm31.3101.3611.4071.2661.261
μ/mm−10.0910.8250.1050.0860.726
F(000)464752520584500
Crystal size/mm30.6 × 0.2 × 0.20.34 × 0.34 × 0.060.3 × 0.2 × 0.20.3 × 0.15 × 0.050.21 × 0.1 × 0.08
Reflections collected528713960934754222016835
Independent reflections6646 [Rint = 0.0958]2646 [Rint = 0.0595]4124 [Rint = 0.0842]2220 4272 [Rint = 0.0451]
Data/restraints/parameters6646/254/4062646/0/2394124/190/4522220/36/1844272/0/277
Goodness-of-fit on F21.0281.0591.0441.0340.857
Final R indexes R1, wR2 [I ≥ 2σ (I)]0.0484, 0.10900.0399, 0.10810.0438, 0.10330.0473, 0.12630.0519, 0.1426
Final R indexes [all data] R1, wR20.0957, 0.13000.0422, 0.11020.0787, 0.11890.0767, 0.13790.0582, 0.1523
Largest diff. peak/hole/e Å−30.25/−0.250.32/−0.190.30/−0.200.356/−0.1960.64/−0.28
a In the refinement, scattering from the disordered acetone molecule was taken into account with the “SQUEEZE” procedure.
Table
Table 2. Hydrogen bonds in the studied cocrystals and in the PPAH pure form.
Table 2. Hydrogen bonds in the studied cocrystals and in the PPAH pure form.
D-H···AH···A/Åd(D···A)/Å∠D-H···A/°Symmetry Transformation for Acceptor
PPA·HBA
O(5)-H(5)···O(1)1.842.6638(18)178.9x, 5/2 − y, z + 1/2
N(2)-H(2A)···O(4)2.102.936(2)163.6x, y + 1, z
N(2)-H(2B)···O(4)2.232.9751(19)144.9−x, 1 − y, 1 − z
O(3)-H(3)···O(2)1.832.6329(17)166.0x, y − 1, z
PPA·2HBA
N(2)-H(2A)···O(1)1.97(3)2.906(3)174(2)2 − x, 1 − y, 1 − z
N(2)-H(2B)···O(2)2.12(3)2.999(3)169(2)1 − x, 1 − y, 1 − z
O(3)-H(3B)···O(2)1.78(3)2.671(2)176(2)3 − x, 2 − y, 1 − z
O(5)-H(5B)···O(6)1.710(17)2.599(2)175(2)x, y, z
O(7)-H(7B)···O(4)1.745(17)2.636(2)174(2)3 − x, 2 − y, 1 − z
O(8)-H(8)···O(3)1.95(3)2.820(2)174(2)1 − x, 1 − y, −z
C(11)-H(11A)···O(6)2.583.407(3)142.62 − x, 1 − y, 1 − z
PPAH
N(2)-H(2)···O(2)2.092.948(2)163.32 − x, 1 − y, 1 − z
C(10)-H(10B)···O(2)2.533.474(3)159.7x − 1, y, z
C(15)-H(15B)···O(1)2.533.387(3)146.12 − x, 1/2 + y, 3/2 − z
PPAH·HBD
N(1)-H(1A)···O(2)2.072.940(4)172.52 − x, 1 − y, 2 − z
N(1)-H(1B)···O(2)2.263.064(4)151.2x − 1, y, z
N(3)-H(3)···O(4)2.072.924(4)161.91 − x, 1 − y, 1 − z
O(1)-H(6)···O(3)1.83(5)2.665(4)170(5)x, y, z
C(2)-H(2)···O(3)2.533.217(5)129.2x, y, z
C(17)-H(17B)···O(4)2.533.423(4)150.2x − 1, y, z
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Marquez, J.; Novikov, E.; Rigin, S.; Fonari, M.S.; Castañeda, R.; Kornilova, T.; Timofeeva, T.V. Exploiting Supramolecular Synthons in Cocrystals of Two Racetams with 4-Hydroxybenzoic Acid and 4-Hydroxybenzamide Coformers. Chemistry 2023, 5, 1089-1100. https://doi.org/10.3390/chemistry5020074

AMA Style

Marquez J, Novikov E, Rigin S, Fonari MS, Castañeda R, Kornilova T, Timofeeva TV. Exploiting Supramolecular Synthons in Cocrystals of Two Racetams with 4-Hydroxybenzoic Acid and 4-Hydroxybenzamide Coformers. Chemistry. 2023; 5(2):1089-1100. https://doi.org/10.3390/chemistry5020074

Chicago/Turabian Style

Marquez, Jason, Egor Novikov, Sergei Rigin, Marina S. Fonari, Raúl Castañeda, Tatiana Kornilova, and Tatiana V. Timofeeva. 2023. "Exploiting Supramolecular Synthons in Cocrystals of Two Racetams with 4-Hydroxybenzoic Acid and 4-Hydroxybenzamide Coformers" Chemistry 5, no. 2: 1089-1100. https://doi.org/10.3390/chemistry5020074

APA Style

Marquez, J., Novikov, E., Rigin, S., Fonari, M. S., Castañeda, R., Kornilova, T., & Timofeeva, T. V. (2023). Exploiting Supramolecular Synthons in Cocrystals of Two Racetams with 4-Hydroxybenzoic Acid and 4-Hydroxybenzamide Coformers. Chemistry, 5(2), 1089-1100. https://doi.org/10.3390/chemistry5020074

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