Communication pubs.acs.org/crystal
Application of Cocrystallization for the Separation of C‑Ethylresorcin[6]arene from C‑Ethylresoricn[4]arene Shan Jiang,† Rahul S. Patil,† Charles L. Barnes,† and Jerry L. Atwood*,† †
Department of Chemistry, University of Missouri, Columbia, Missouri 65211, United States S Supporting Information *
ABSTRACT: Cocrystals formed from macrocyclic compounds such as calixarenes are particularly useful for understanding various host−guest interactions and solid state properties. Resorcinarenes, a subclass of calixarenes, are also useful for the construction of cocrystalline materials because of their unique bowl shape, decorated with eight hydroxyl groups. Here we investigate the separation of hexameric C-ethylresoricn[6]arene from its tetrameric homologues C-ethylresorcin[4]arene via cocrystallization with 4,4′bipyridine (Scheme 1). The effect of the stoichiometric ratio of the components and the solvent of crystallization on the separation of macrocycles and on the formation of a particular cocrystal is also discussed.
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bonds, cation−π interactions, π−π interactions, and van der Waals forces between two or more different molecules in a given medium.14 Thus, these noncovalent interactions are influenced by molecular shape and functional groups on the molecules involved in the cocrystallization.15 Macrocyclic compounds such as C-alkylresorcin[4]arenes (4RsCn) and C-alkylpyrogallol[4]arenes (4-PgCn) are useful for construction of supramolecular organic frameworks where the approach of cocrystallization is often used.16−21 4-RsCn and 4PgCn have unique bowl-shaped structures in which the upper rim of the bowl has 8 or 12 hydroxyl groups, respectively, while the lower rim contains four C-alkyl chains. These structural features of 4-RsCn and 4-PgCn offer a variety of intermolecular interactions such as hydrogen bonds through the hydroxyl groups, π−π interactions through the aromatic resorcinol or pyrogallol, H−π interactions through π-electron cloud of the 4RsCn/4-PgCn bowl, and van der Waals forces through the Calkyl chains.18−21 Usually, crystallization of 4-RsCn or 4-PgCn entities yields bilayer, hexameric, or tubular arrangements of these macrocycles in the crystalline solid state.22,23 However, cocrystallization of 4-RsCn and 4-PgCn with organic molecules such as 4,4′-bipyridine (bpy) results in a variety of framework architectures ranging from extended bilayers, wave-like arrangements, skewed bricks, extended capsules, and extended 1D to 2D frameworks.18,24−30 Cocrystallization of 4-RsCn/4-PgCn with various small molecules is also employed to investigate host−guest interactions, and gas sorption ability of framework materials.17,31−35 However, higher homologues of 4-RsCn/4PgCn such as C-alkylresorcin[5]arenes and C-alkyresorcin[6]-
INTRODUCTION Cocrystals are formed by combining two or more molecular species in a single crystal lattice without making or breaking covalent bonds.1 Recently, cocrystallization is emerging as an alternative approach to improve the physical or chemical properties of crystalline materials. Particularly for pharmaceutical solids, cocrystallization may improve solubility, stability, dissolution rate, and dielectric properties of active pharmaceutical ingredients (APIs).1−3 Apart from pharmaceuticals, cocrystals also have potential applications in scientific fields such as green chemistry,4,5 electronics,6,7 energy storage,8,9 organic synthesis/separation,10,11 and luminescent materials.12,13 Formation of cocrystals results from noncovalent intermolecular interactions such as hydrogen bonds, halogen Scheme 1. Components of Cocrystallization
Received: May 16, 2017 Revised: June 28, 2017 Published: June 30, 2017 © XXXX American Chemical Society
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DOI: 10.1021/acs.cgd.7b00691 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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Figure 1. (A) Intermolecular hydrogen bonding interactions in 1. (B) Wave-like arrangement of 4-RsC2 and bpy in the extended structure of 1. (Color codes: Gray, Carbon; Red, Nitrogen; Blue, Nitrogen. Hydrogen atoms are removed for clarity.)
hydroxyl groups of 4-RsC2. These intramolecular hydrogen bonding interactions are responsible for holding a cone shape of 4-RsC2 with the rccc configuration. Three hydroxyl groups of 4-RsC2 form O−H···N (2.65−2.72 Å) hydrogen bonds with three slightly tilted bpy over the 4-RsC2 bowl where two bpy ligands interact with hydroxyl groups on one resorcinol and the third bpy interacts with the hydroxyl group of oppositely placed resorcinol on the same 4-RsC2 (Figure 1A). The other end of the three bpy ligands also form similar O−H···N hydrogen bonds with two 4-RsC2, and thus resulted in a wave-like arrangement of 4-RsC2 and bpy in the crystal structure (Figure 1B). One water molecule forms an O−H···O (2.62 Å) hydrogen bond with a hydroxyl group of the parent 4-RsC2 (Figure 1A). The same water molecule forms similar O−H···O (2.78 Å) and O−H···N (2.77 Å) hydrogen bonds with the hydroxyl group of neighboring 4-RsC2 and with a bpy, respectively (Figure S2). Thus, the water molecule functions as a bridging agent by connecting two 4-RsC2 macrocycles to each other, and by connecting 4-RsC2 to a bpy through hydrogen bonding interactions (Figure S2). The head-to-tail arrangement of the 4-RsC2 molecules resulted in the formation of stacks of 4-RsC2 along the [100] crystallographic direction (Figure S3). An acetonitrile molecule interacts with the πelectron cloud of the cone-shaped 4-RsC2 through a CH3-π interaction (Figure 1A). Thus, acetonitrile molecules occupy space between the head-to-tail arranged 4-RsC2. The unique arrangement of components in cocrystal 1 led to the cocrystallization of the RsCn mixture with bpy in more polar solvents such as methanol. Thus, single crystals of cocrystal 2 [(6-RsC2) 4(bpy)] were grown by reacting the RsC2 mixture with bpy in methanol, followed by slow evaporation of the solvent over 7−10 days (detailed cocrystal synthesis procedure in SI).
arenes (Scheme 1) have not been explored much for construction of supramolecular frameworks since the synthesis and separation of these higher homologues are difficult.36 A typical acid-catalyzed condensation reaction for synthesis of resorcinarenes produces thermodynamically stable 4-RsCn; however, other oligomers and stereoisomers are also formed in minor concentrations.36,37 Previous studies have explained that it is easier to functionalize and purify a reaction mixture than isolation of each oligomer from the mixture.38,39 In our recent article, we applied the cocrystallization technique for separation of hexameric C-ethylresorcin[6]arenes (4-RsC2) from Cethylresorcin[4]arenes (6-RsC2) using 1-(2-pyridylazo)-2 naphthol.11 Thus, to extend this class of cocrystals based on RsCn, we separated tetrameric 4-RsC2 from hexameric 6-RsC2 and in situ synthesized two novel cocrystals of each macrocycle with bpy. The effects of solvent and stoichiometric ratio of components on the structural arrangements of the cocrystals are also investigated here.
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RESULT AND DISCUSSION The conventional acid catalyzed condensation reaction of resorcinol with propionaldehyde produces a mixture of tetrameric 4-RsC2 and hexameric 6-RsC2.40 The presence of both macrocycles is verified with 1H NMR spectroscopy of reaction product (RsC2 mixture) (Figure S1). In 1H NMR of RsC2 mixture, triplets centered at 4.17 and 4.32 ppm correspond to the hydrogen atom on the bridging methine (CH) group of 4-RsC2 and 6-RsC2 respectively (Figure S1). Single crystals of cocrystal 1 [(4-RsC2) 2(bpy) (MeCN) (water)] were grown by reacting the RsC2 mixture with bpy and acetonitrile in the presence of a trace amount of water (detailed cocrystal synthesis procedure in SI). The crystal structure of 1 displays a cone-shaped 4-RsC2 with four O−H··· O (2.73−2.82 Å) intramolecular hydrogen bonds between the B
DOI: 10.1021/acs.cgd.7b00691 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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Figure 2. (A) Intermolecular hydrogen bondin interactions among 6-RsC2 macrocycles in 2. (B) Intermolecular O−H···N bydrogen bonding interactions between 6-RsC2 and bpy molecules in 2. (Color codes: Gray, Carbon; Red, Nitrogen; Blue, Nitrogen; Hydrogen atoms are removed for clarity.)
Crystal structure of 2 consists of 6-RsC2 in r-cis−trans−cis− trans−cis conformation; however, there are no intramolecular hydrogen bonding interactions between hydroxyl groups of 6RsC2. Eight hydroxyl groups of 6-RsC2 form O−H···O (2.80− 2.89 Å) hydrogen bonds with hydroxyl groups of four adjacent 6-RsC2 (Figure 2A). Thus, each 6-RsC2 links with four 6-RsC2 though eight O−H···O hydrogen bonds (Figure 2A). These intermolecular interactions between 6-RsC2 molecules exhibit a continuous 2D arrangement of hydrogen bonded 6-RsC2 along the [100] crystallographic axis (Figure 2A). A hydroxyl group on each resorcinol of the 6-RsC2 also forms O−H···N (2.71− 2.81 Å) hydrogen bonds with bpy. Therefore, each 6-RsC2 interacts with eight bpy ligands through hydrogen bonds (Figure 2B). Other ends of these eight bpy molecules are hydrogen bonded to four 6-RsC2 through similar O−H···N interactions and thus bpy functions as a bridging agent, connecting one 6-RsC2 with four 6-RsC2 molecules (Figure 2B). This intermolecular interaction between 6-RsC2 and bpy forms a 2D framework with alternate arrangement of components. Thus, crystal structure of 2 has two continuous 2D hydrogen bonding arrays formed among 6-RsC2, and between 6-RsC2 and bpy (Figure 2A,B). Formation of two unique cocrystals causes the separation of 6-RsC2 from 4-RsC2 since the crystal structure of 2 contains 6RsC2 and bpy, whereas 4-RsC2 remains in solution which can easily be recovered by filtration of cocrystal 2. Thus, to optimize this separation process, the effect of change in the stoichiometric ratio of components on the separation process and on the formation of cocrystals was evaluated. Experimental conditions similar to those of cocrystal 1 and cocrystal 2 were employed to investigate the effect of variation on stoichiometric ratio. However, this change in the stoichiometric ratio of major components (RsC2 mixture and bpy) resulted in the formation of similar cocrytals, either cocrystal 1 or 2. Powder X-ray diffraction (PXRD) analysis was used to characterize the bulk crystalline solid obtained in these experiments. Bpy forms cocrystal 1 with 4-RsC2 in acetonitrile only in the lower stoichiometric ratio of 1:1 and 1:2 (RsC2 mixture:bpy) (Table 1 and Figure S4). However, higher stoichiometric ratios of the RsC2 mixture:bpy (1:3, 1:4), resulted in the formation of cocrystal 2 (Table 1 and Figure S4). A more polar solvent such as methanol also results in the formation of cocrystal 2,
Table 1. Summary of Experiments stoichiometric ratio (RsCn: bpy)
solvent
cocrystal
1:1 1:2 1:3 1:4 1:1 1:2 1:3 1:4
Acetonitrile Acetonitrile Acetonitrile Acetonitrile Methanol Methanol Methanol Methanol
1 1 2 2 2 2 2 2
irrespective of the stoichiometric ratio between the RsC2 mixture:bpy (Table 1 and Figure S5). Formation of two distinct cocrystals resulted from the difference in the solubility and molecular structure of 4-RsC2 and 6-RsC2. 4-RsC2 has eight hydroxyl groups; however, 6-RsC2 has 12 hydroxyl groups. Thus, bpy reacts with 4-RsC2 in lower stoichiometric ratios (1:1 and 1:2) compared to 6-RsC2, which interacts with bpy at higher stoichiometric ratios (1:3, 1:4) in acetonitrile. The use of a polar solvent increases the solubility of 6-RsC2, and thus results in the formation of cocrystal 2, irrespective of the stoichiometric ratio. Therefore, formation of particular cocrystals and ultimately the separation of 6-RsC2 from 4RsC2 is greatly influenced by the type of solvent and the stoichiometric ratio of RsCn mixture:bpy.
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CONCLUSION The cocrystal of tetrameric 4-RsC2 with bpy has a unique wavelike arrangement of 4-RsC2 and bpy; however, the cocrystal of hexameric 6-RsC2 with bpy has a 2D alternate arrangement of 6-RsC2 and bpy. The higher number of hydroxyl groups on 6RsC2 favors the formation of cocrystal 2 with a higher stoichiometric ratio in acetonitrile. More polar solvents such as methanol exhibit the separation of 6-RsC2 from 4-RsC2 and simultaneously leads to formation of cocrystal 2, irrespective of the stoichiometric ratio of the components. This is explained by the increased solubility of 6-RsC2 in methanol compared to acetonitrile. C
DOI: 10.1021/acs.cgd.7b00691 Cryst. Growth Des. XXXX, XXX, XXX−XXX
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00691. Synthesis of resorcinarenes and cocrystals; 1H NMR spectroscopy; crystallographic data; structural diagrams; PXRD data; hydrogen bonding data (PDF) Accession Codes
CCDC 1536768 and 1536777 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jerry L. Atwood: 0000-0002-3350-9618 Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.cgd.7b00691 Cryst. Growth Des. XXXX, XXX, XXX−XXX
