Multicomponent Crystal of Metformin and Barbital: Design,Crystal Structure Analysis and Characterization

The formation of most multicomponent crystals relies on the interaction of hydrogen bonds between the components, so rational crystal design based on the expected hydrogen-bonded supramolecular synthons was employed to establish supramolecular compounds with desirable properties. This theory was put into practice for metformin to participate in more therapeutic fields to search for a fast and simple approach for the screening of candidate crystal co-formers. The prediction of intermolecular synthons facilitated the successful synthesis of a new multicomponent crystal of metformin (Met) and barbital (Bar) through an anion exchange reaction and cooling crystallization method. The single crystal X-ray diffraction analysis demonstrated the hydrogen bond-based ureide/ureide and guanidine/ureide synthons were responsible for the self-assembly of the primary structural motif and extended into infinite supramolecular heterocatemeric structures.     

Solvent exchange in thermally stable resorcinarene nanotubes

The assembly of C-methyl resorcinarene into a tubular supramolecular solid-state structure, its thermal stability, and its hosting properties are reported. Careful control of the crystallisation conditions of C-methyl resorcinarene and 1,4-dimethyl-1,4-diazoniabicyclo[2.2.2]octane (1,4-dimethyl DABCO) dibromide leads to a formation of two crystallographically different, but structurally very similar, solid-state nanotube structures. These structures undergo a remarkable variety of supramolecular interactions, which lead to the formation of 0.5 nm diameter nonpolar tubes through the crystal lattice. The formation of these tubes is templated by suitably sized small alcohols, namely, n-propanol, 2-propanol, or n-butanol. The self-assembly involves close pi...pi interactions between the adjacent resorcinarenes, and C--H...pi and cation...pi interactions between the resorcinarenes and the guest 1,4-dimethyl DABCO dications. The crystals of these supramolecular tube structures are thermally very stable and the included solvent alcohol can be removed from the tubes without breaking the single-crystalline structure of the assembly. After removal of the solvent molecules the tubes can be filled with other small, less polar solvent molecules such as dichloromethane.     

Porphyrin/Ionic‐Liquid Co‐assembly Polymorphism Controlled by Liquid–Liquid Phase Separation

Understanding and controlling multicomponent co‐assembly is of primary importance in different fields, such as materials fabrication, pharmaceutical polymorphism, and supramolecular polymerization, but these aspects have been a long‐standing challenge. Herein, we discover that liquid–liquid phase separation (LLPS) into ion‐cluster‐rich and ion‐cluster‐poor liquid phases is the first step prior to co‐assembly nucleation based on a model system of water‐soluble porphyrin and ionic liquids. The LLPS‐formed droplets serve as the nucleation precursors, which determine the resulting structures and properties of co‐assemblies. Co‐assembly polymorphism and tunable supramolecular phase transition behaviors can be achieved by regulating the intermolecular interactions at the LLPS stage. These findings elucidate the key role of LLPS in multicomponent co‐assembly evolution and enable it to be an effective strategy to control co‐assembly polymorphism as well as supramolecular phase transitions.     

Construction of hydrogen-bonded ternary organic crystals derived from L-tartaric acid and their application to enantioseparation of secondary alcohols

Ternary organic crystals consisting of an L-tartaric acid-derived dicarboxylic acid, a commercially available achiral diamine, and a chiral secondary alcohol have been developed and characterized by X-ray crystallography. 1D, 2D, and 3D hydrogen-bonded supramolecular networks were constructed, depending on the structure of the diamine used. Benzylic and aliphatic secondary alcohols were enantioselectively incorporated into the crystal and were successfully enantioseparated with up to 86 and 79% enantiomeric excess (ee), respectively. Selective incorporation of one enantiomer of 2-butanol, which is a small chiral aliphatic alcohol, was achieved by the cooperative effects of hydrogen bonds, CH···π interactions, and van der Waals interactions between the guest and host molecules, with the aid of two water molecules. The high host potential of the binary supramolecular system is mainly attributed to the skewed conformation of two rigid aromatic groups of tartaric acid derivatives, which prevents dense packing of the molecules and enhances the formation of multicomponent inclusion crystals.     

Luminescent Metallacycle‐Cored Liquid Crystals Induced by Metal Coordination

Two rhomboidal metallacycles based on metal‐coordination‐driven self‐assembly are presented. Because metal‐coordination interactions restrict the rotation of phenyl groups on tetraphenylethene units, these metallacycles were emissive both in solution and in solid state, and their aggregation‐induced emission properties were well‐retained. Moreover, the rhomboidal metallacyclic structures offer a platform for intermolecular packing beneficial for the formation of liquid crystalline phases. Therefore, although neither of building blocks shows mesogenic properties, both thermotropic and lyotropic (in DMF) mesophases were observed in one of metallacycles, indicating that mesophases could be induced by metal‐coordination interactions. This study not only reveals the mechanism for the formation of cavity‐cored liquid crystals, but also provides a convenient approach to preparing supramolecular luminescent liquid crystals, which will serve as good candidates for chemo sensors and liquid crystal displays.     

Supramolecular [60]Fullerene Liquid Crystals Formed By Self‐Organized Two‐Dimensional Crystals

Fullerene‐based liquid crystalline materials have both the excellent optical and electrical properties of fullerene and the self‐organization and external‐field‐responsive properties of liquid crystals (LCs). Herein, we demonstrate a new family of thermotropic [60]fullerene supramolecular LCs with hierarchical structures. The [60]fullerene dyads undergo self‐organization driven by π–π interactions to form triple‐layer two‐dimensional (2D) fullerene crystals sandwiched between layers of alkyl chains. The lamellar packing of 2D crystals gives rise to the formation of supramolecular LCs. This design strategy should be applicable to other molecules and lead to an enlarged family of 2D crystals and supramolecular liquid crystals.     

Thermotropic Liquid Crystals Formed by Intermolecular Hydrogen Bonding Interactions

The role of hydrogen bonding in the formation or stabilization of liquid crystalline phases has only recently been appreciated. Following the first, wellestablished examples of liquid crystal formation from the dimerization of aromatic carboxylic acids, through hydrogen bonding, several classes of compounds have recently been synthesized, the liquid crystalline behavior of which is also dependent on intermolecular hydrogen bonds between similar or dissimilar molecules. In this review the main classes of compounds exhibiting liquid crystallinity due to hydrogen bonding are presented to show the diversity of organic compounds that can be used as building elements in liquid crystals. The molecules are either of the rigid-rod anisotropic or amphiphilic types such as molecules appropriately functionalized with pyridyl and carboxyl groups, whose interaction leads to the formation of liquid crystals; amphiphilic carbohydrates and amphiphilic and bolaamphiphilic compounds with multiple hydroxyl groups whose dimerization or association is indispensable for the formation of liquid crystals; and certain amphiphilic carboxylic acids with monomeric or polymeric mesogens and amphiphilic-type compounds bearing different moieties, whose interaction may lead to the formation of mesomorphic compounds. Associated with the macroscopic display of liquid crystalline phases is the supramolecular structure, and therefore rather extended discussion of these structures are included in this review.     

Access to Metastable Gel States Using Seeded Self‐Assembly of Low‐Molecular‐Weight Gelators

Here we report on how metastable supramolecular gels can be formed through seeded self‐assembly of multicomponent gelators. Hydrazone‐based gelators decorated with non‐ionic and anionic groups are formed in situ from hydrazide and aldehyde building blocks, and lead through multiple self‐sorting processes to the formation of heterogeneous gels approaching thermodynamic equilibrium. Interestingly, the addition of seeds composing of oligomers of gelators bypasses the self‐sorting processes and accelerates the self‐assembly along a kinetically favored pathway, resulting in homogeneous gels of which the network morphologies and gel stiffness are markedly different from the thermodynamically more stable gel products. Importantly, over time, these metastable homogeneous gel networks are capable of converting into the thermodynamically more stable state. This seeding‐driven formation of out‐of‐equilibrium supramolecular structures is expected to serve as a simple approach towards functional materials with pathway‐dependent properties.     

Crystal Structure of Quinine: The Effects of Vinyl and Methoxy Groups on Molecular Assemblies of Cinchona Alkaloids Cannot Be Ignored

Quinine, one of Cinchona alkaloids, has been of great interest from medical, synthetic, and supramolecular viewpoints. However, unaccountably, the guest‐free (GF) crystal of quinine containing no solvent or other molecules has not been reported for nearly three decades, although GF crystals of other Cinchona alkaloids, such as quinidine, cinchonidine, and cinchonine, are already known. In this study, we successfully revealed the crystal structure of quinine, which belongs to the P2₁ space group with the cell parameters of a=6.0587(1), b=19.2492(5), c=22.2824(7) Å, β=92.1646(11)°, and V=2596.83(12) ų. Interestingly, the crystal has three crystallographically independent molecules in the cell (Z′=3) that are connected through a N(quinoline)???H? O hydrogen bond to form a pseudo three‐two‐fold (3₂) double‐helical motif. The helical motif is completely different from those observed in GF crystals of other Cinchona alkaloids. Hierarchical comparison on the crystal structures of a series of Cinchona alkaloids including quinine clearly demonstrated that only small structural differences of a molecule, particularly the position of the vinyl group, cause a significant variety of assembly manner in the crystalline state. There have been no reports systematically demonstrating such steric effect in crystals of Cinchona alkaloids, and, therefore, the present system contributes to the design of desired functional crystal structures.     

Modular Columnar Supramolecular Polymers as Scaffolds for Biomedical Applications

Self‐assembly of discotic molecules into supramolecular polymers offers a flexible approach for the generation of multicomponent one‐dimensional columnar architectures with tuneable biomedical properties. Decoration with ligands induces specific binding of the self‐assembled scaffold to biological targets. The modular design allows the easy co‐assembly of different discotics for the generation of probes for targeted imaging and cellular targeting with adjustable ligand density and composition.     

Supramolecular hydrogen-bonded liquid crystals

The role of hydrogen-bonding interactions in the formation and/or stabilization of liquid crystalline phases has been recognized in recent years and significant work has been conducted. Following the first and well-established examples of liquid crystal formation through the dimerization of aromatic carboxylic acids, several classes of compounds have been prepared by the interaction of complementary molecules, the liquid crystalline behaviour of which is crucially dependent on the structure of the resulting supramolecular systems. In this review the main classes of liquid crystals prepared through hydrogen-bonding interactions are presented, with the aim of establishing, in the first place, the diversity of organic compounds that can be used as building elements in the process of liquid crystal formation. Rigid-rod anisotropic or amphiphilic-type molecules, appropriately functionalized with recognizable moieties, interact in the melt or in solution and lead to the formation of supramolecular complexes that may exhibit thermotropic liquid crystalline character. Depending on the nature, number and position of the groups able to form hydrogen bonds, a diversity of supramolecular structures, both dimeric and polymeric, have been obtained, affording in turn various liquid crystalline phases. The structure and stability of these hydrogen-bonded supramolecular complexes and their relation to the observed liquid crystalline phases are the main topics of this review.     

Supramolecular hydrogen-bonded liquid crystals

The role of hydrogen-bonding interactions in the formation and/or stabilization of liquid crystalline phases has been recognized in recent years and significant work has been conducted. Following the first and well-established examples of liquid crystal formation through the dimerization of aromatic carboxylic acids, several classes of compounds have been prepared by the interaction of complementary molecules, the liquid crystalline behaviour of which is crucially dependent on the structure of the resulting supramolecular systems. In this review the main classes of liquid crystals prepared through hydrogen-bonding interactions are presented, with the aim of establishing, in the first place, the diversity of organic compounds that can be used as building elements in the process of liquid crystal formation. Rigid-rod anisotropic or amphiphilic-type molecules, appropriately functionalized with recognizable moieties, interact in the melt or in solution and lead to the formation of supramolecular complexes that may exhibit thermotropic liquid crystalline character. Depending on the nature, number and position of the groups able to form hydrogen bonds, a diversity of supramolecular structures, both dimeric and polymeric, have been obtained, affording in turn various liquid crystalline phases. The structure and stability of these hydrogen-bonded supramolecular complexes and their relation to the observed liquid crystalline phases are the main topics of this review.     

Supramolecular engineering of intrinsic and extrinsic porosity in covalent organic cages

Control over pore size, shape, and connectivity in synthetic porous materials is important in applications such as separation, storage, and catalysis. Crystalline organic cage molecules can exhibit permanent porosity, but there are few synthetic methods to control the crystal packing and hence the pore connectivity. Typically, porosity is either 'intrinsic' (within the molecules) or 'extrinsic' (between the molecules)--but not both. We report a supramolecular approach to the assembly of porous organic cages which involves bulky directing groups that frustrate the crystal packing. This generates, in a synthetically designed fashion, additional 'extrinsic' porosity between the intrinsically porous cage units. One of the molecular crystals exhibits an apparent Brunauer-Emmett-Teller surface area of 854 m(2) g(-1), which is higher than that of unfunctionalized cages of the same dimensions. Moreover, connectivity between pores, and hence guest uptakes, can be modulated by the introduction of halogen bonding motifs in the cage modules. This suggests a broader approach to the supramolecular engineering of porosity in molecular organic crystals.     

Halogen bonding-driven formation of supramolecular macrocycles and double helix

Halogen bonding has been used to hold two hydrogen bonded aromatic amide foldamers to form supramolecular macrocycles.     

Self‐Healing Behavior in a Thermo‐Mechanically Responsive Cocrystal during a Reversible Phase Transition

The molecular‐level motions of a coronene‐based supramolecular rotator are amplified into macroscopic changes of crystals by co‐assembly of coronene and TCNB (1,2,4,5‐tetracyanobenzene) into a charge‐transfer complex. The as‐prepared cocrystals show remarkable self‐healing behavior and thermo‐mechanical responses during thermally‐induced reversible single‐crystal‐to‐single‐crystal (SCSC) phase transitions. Comprehensive analysis of the microscopic observations as well as differential scanning calorimetry (DSC) measurements and crystal habits reveal that a thermally‐reduced‐rate‐dependent dynamic character exists in the phase transition. The crystallographic studies show that the global similarity of the packing patterns of both phases with local differences, such as molecular stacking sequence and orientations, should be the origin of the self‐healing behavior of these crystals.     

Crystallization Force—A Density Functional Theory Concept for Revealing Intermolecular Interactions and Molecular Packing in Organic Crystals

Organic molecules are prone to polymorphic formation in the solid state due to the rich diversity of functional groups that results in comparable intermolecular interactions, which can be greatly affected by the selection of solvent and other crystallization conditions. Intermolecular interactions are typically weak forces, such as van der Waals and stronger short‐range ones including hydrogen bonding, that are believed to determine the packing of organic molecules during the crystal‐growth process. A different packing of the same molecules leads to the formation of a new crystal structure. To disclose the underlying causes that drive the molecule to have various packing motifs in the solid state, an electronic concept or function within the framework of conceptual density functional theory has been developed, namely, crystallization force. The concept aims to describe the local change in electronic structure as a result of the self‐assembly process of crystallization and may likely quantify the locality of intermolecular interactions that directs the molecular packing in a crystal. To assess the applicability of the concept, 5‐methyl‐2‐[(2‐nitrophenyl)amino]‐3‐thiophenecarbonitrile, so‐called ROY, which is known to have the largest number of solved polymorphs, has been examined. Electronic calculations were conducted on the seven available crystal structures as well as on the single molecule. The electronic structures were analyzed and crystallization force values were obtained. The results indicate that the crystallization forces are able to reveal intermolecular interactions in the crystals, in particular, the close contacts that are formed between molecules. Strong correlations exist between the total crystallization force and lattice energy of a crystal structure, further suggesting the underlying connection between the crystallization force and molecular packing.     

Influence of functional groups on the self-assembly of liquid crystals

Functional groups in the molecule play an important role in the molecular o rganization process.To reveal the influence of functional groups on the self-assembly at interface,herein,the self-assembly structures of three liquid crystal molecules,which only differ in the functional groups,are explicitly characterized by using scanning tunneling microscopy(STM).The high-resolution STM images demonstrate the difference between the supramolecular assembly structures of three liquid crystal molecules,which attribute to the hydrogen bonding interaction and π-π stacking interaction between different functional groups.The density functional theory(DFT) results also confirm the influence of these functional groups on the self-assemblies.The effort on the self-assembly of liquid crystal molecules at interface could enhance the understanding of the supramolecular assembly mechanism and benefit the further application of liquid crystals.     

Water‐Binding‐Mediated Gelation/Crystallization and Thermosensitive Superchirality

Determination of molecular structural parameters of hydrophobic cholesterol–naphthalimide conjugates for water binding capabilities as well as their moisture‐sensitive supramolecular self‐assembly were revealed. Water binding was a key factor in leading trace water‐induced crystallization against gelation in apolar solvent. Ordered water molecules entrapped in self‐assembly arrays revealed by crystal structures behave as hydrogen‐bonding linkers to facilitate three‐dimensional growth into crystals rather than one‐dimensional gel nanofibers. Water binding was also reflected on the supramolecular chirality inversion of vesicle self‐assembly in aqueous media via heating‐induced dehydration. Structural parameters that favor water binding were evaluated in detail, which could help rationally design organic building units for advancing soft materials, crystal engineering, and chiral recognition.     

New simulation model of multicomponent crystal growth and inhibition

We review a novel computational model for the study of crystal structures both on their own and in conjunction with inhibitor molecules. The model advances existing Monte Carlo (MC) simulation techniques by extending them from modeling 3D crystal surface patches to modeling entire 3D crystals, and by including the use of "complex" multicomponent molecules within the simulations. These advances makes it possible to incorporate the 3D shape and non-uniform surface properties of inhibitors into simulations, and to study what effect these inhibitor properties have on the growth of whole crystals containing up to tens of millions of molecules. The application of this extended MC model to the study of antifreeze proteins (AFPs) and their effects on ice formation is reported, including the success of the technique in achieving AFP-induced ice-growth inhibition with concurrent changes to ice morphology that mimic experimental results. Simulations of ice-growth inhibition suggest that the degree of inhibition afforded by an AFP is a function of its ice-binding position relative to the underlying anisotropic growth pattern of ice. This extended MC technique is applicable to other crystal and crystal-inhibitor systems, including more complex crystal systems such as clathrates.     

Survival of the Fittest: Competitive Co‐crystal Reactions in the Ball Mill

The driving forces triggering the formation of co‐crystals under milling conditions were investigated by using a set of multicomponent competitive milling reactions. In these reactions, different active pharmaceutical ingredients were ground together with a further compound acting as coformer. The study was based on new co‐crystals including the coformer anthranilic acid. The results of the competitive milling reactions indicate that the formation of co‐crystals driven by intermolecular recognition are influenced and inhibited by kinetic aspects including the formation of intermediates and the stability of the reactants.