Crystal engineering: a holistic view

Crystal engineering, the design of molecular solids, is the synthesis of functional solid-state structures from neutral or ionic building blocks, using intermolecular interactions in the design strategy. Hydrogen bonds, coordination bonds, and other less directed interactions define substructural patterns, referred to in the literature as supramolecular synthons and secondary building units. Crystal engineering has considerable overlap with supramolecular chemistry, X-ray crystallography, materials science, and solid-state chemistry and yet it is a distinct discipline in itself. The subject goes beyond the traditional divisions of organic, inorganic, and physical chemistry, and this makes for a very eclectic blend of ideas and techniques. The purpose of this Review is to highlight some current challenges in this rapidly evolving subject. Among the topics discussed are the nature of intermolecular interactions and their role in crystal design, the sometimes diverging perceptions of the geometrical and chemical models for a molecular crystal, the relationship of these models to polymorphism, knowledge-based computational prediction of crystal structures, and efforts at mapping the pathway of the crystallization reaction.     

Crystal Engineering with Multipoint Halogen Bonding: Double Two-Point Donors and Acceptors at Work

The combination of singly or doubly bidentate halogen-bond donors with double bidentate acceptors was investigated as a supramolecular synthon in crystal engineering. The crystal topologies obtained feature novel halogen-bonding motifs like double two-point recognition and infinite chains or networks based on two-point interactions. Induced conformational changes in the double bidentate halogen-bond donors could be exploited to obtain different 1D and 2D networks. All solid-state studies were accompanied by DFT calculations to predict and rationalize the outcome.     

氢键在现代化学中的作用

在各种分子间相互作用中,氢键占有很特殊的地位,被称作为超分子化学中的万能相互作用。讨论了氢键在超分子、自组装、分子识别、晶体工程、材料化学和催化过程等现代化学领域中的作用。     

Halogen bonding in supramolecular chemistry

Halogen bonding is the noncovalent interaction where halogen atoms function as electrophilic species. The energetic and geometrical features of the interaction are described along with the atomic characteristics that confer molecules with the specific ability to interact through this interaction. Halogen bonding has an impact on all research fields where the control of intermolecular recognition and self-assembly processes plays a key role. Some principles are presented for crystal engineering based on halogen-bonding interactions. The potential of the interaction is also shown by applications in liquid crystals, magnetic and conducting materials, and biological systems.     

一类新型超分子主体——硫代杯芳烃的研究进展

硫代杯芳烃是一类以硫原子取代桥联亚甲基的新型杯芳烃, 作为新一代超分子砌块, 在分子识别、超分子自组装、晶体工程和纳米材料等方面都获得了广泛的应用, 已成为当今超分子化学研究的新热点. 综述了硫代杯芳烃及其衍生物的合成、功能化修饰及应用方面的研究进展.     

Supramolecular [6]chochin and "Big Mac" made from chiral Piedfort assemblies

Facile chemical synthesis of the natural chiral-pool-derived host 1 and its subsequent crystallization ("supramolecular synthesis") from different solvents yielded crystalline assemblies. Crystal structure determinations of five of the so formed solvent-inclusion compounds (1 a-1 e) reveal hexagonal symmetries in four cases. The structural characteristics of these chiral host-guest ensembles with varying stoichiometries can be best described as assemblies formed through intra-pair hydrogen bridges of host molecules into Piedfort pairs of differing complexity. Hitherto undescribed, these Piedfort pairs also form even larger regular assemblies that we designate "Big Mac"-like shapes. In the only nonhexagonal case, six independent host molecules form a huge supramolecular analogue of [6]benzocyclophane, also known as [6]chochin, extending this giant supermolecule through intermolecular hydrogen bonds into macroscopic (mm-size) dimensions. As all these crystals are inherently chiral, and new model systems for solid-state applications can be envisaged.     

Supramolecular Chemistry—Scope and Perspectives Molecules,Supermolecules, and Molecular Devices (Nobel Lecture)

Supramolecular chemistry is the chemistry of the intermolecular bond, covering the structures and functions of the entities formed by association of two or more chemical species. Molecular recognition in the supermolecules formed by receptor-substrate binding rests on the principles of molecular complementarity, as found in spherical and tetrahedral recognition, linear recognition by coreceptors, metalloreceptors, amphiphilic receptors, and anion coordination. Supramolecular catalysis by receptors bearing reactive groups effects bond cleavage reactions as well as synthetic bond formation via cocatalysis. Lipophilic receptor molecules act as selective carriers for various substrates and make it possible to set up coupled transport processes linked to electron and proton gradients or to light. Whereas endoreceptors bind substrates in molecular cavities by convergent interactions, exoreceptors rely on interactions between the surfaces of the receptor and the substrate; thus new types of receptors, such as the metallonucleates, may be designed. In combination with polymolecular assemblies, receptors, carriers, and catalysts may lead to molecular and supramolecular devices, defined as structurally organized and functionally integrated chemical systems built on supramolecular architectures. Their recognition, transfer, and transformation features are analyzed specifically from the point of view of molecular devices that would operate via photons, electrons, or ions, thus defining fields of molecular photonics, electronics, and ionics. Introduction of photosensitive groups yields photoactive receptors for the design of light-conversion and charge-separation centers. Redox-active polyolefinic chains represent molecular wires for electron transfer through membranes. Tubular mesophases formed by stacking of suitable macrocyclic receptors may lead to ion channels. Molecular self-assembling occurs with acyclic ligands that form complexes of double-helical structure. Such developments in molecular and supramolecular design and engineering open perspectives towards the realization of molecular photonic, electronic, and ionic devices that would perform highly selective recognition, reaction, and transfer operations for signal and information processing at the molecular level.     

气相色谱中的超分子化学问题：Ⅰ.气相色谱与超分子化学的关系

超分子化学是有关超分子体系结构和功能的化学，超分子体系是由多个分子作用联系起来的实体，分子识别是形成超分本系的基本特征，本文从分子识别的角度，探讨了气相色谱学中超分子化学问题，并详细地评述了冠醚、液晶、环表固定液的分子识别机理的研究状况，最后，作者们大致展望了色谱研究超分子问题的前景，并且认为在多人工作基础上会产生一门新科学－超分子色谱学。     

A Combined Experimental and Computational Study of Halogen and Hydrogen Bonding in Molecular Salts of 5-Bromocytosine

Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical and pharmaceutical relevance of these compounds, six different crystals containing proton-transfer derivatives of 5-bromocytosine are prepared and analyzed in the solid-state by single crystal X-ray diffraction. All six compounds are organic salts, with proton transfer occurring to the N_imino atom of the pyridine ring. Experimental results are then complemented with Hirshfeld surface analysis to quantitively evaluate the contribution of different intermolecular interactions in the crystal packing. Furthermore, theoretical calculations, based on different arrangements of molecules extracted from the crystal structure determinations, are carried out to analyze the formation mechanism of halogen bonds (XBs) in these compounds and provide insights into the nature and strength of the observed interactions. The results show that the supramolecular architectures of the six molecular salts involve extensive classical intermolecular hydrogen bonds. However, in all but one proton-transfer adducts, weak to moderate XBs are revealed by C–Br^…O short contacts between the bromine atom in the fifth position, which acts as XB donor (electron acceptor). Moreover, the lone pair electrons of the oxygen atom of adjacent pyrimidine nucleobases and/or counterions or water molecules, which acts as XB acceptor (electron donor).     

Concurring Chalcogen- and Halogen-Bonding Interactions in Supramolecular Polymers for Crystal Engineering Applications

The engineering of crystalline molecular solids through the simultaneous combination of distinctive non-covalent interactions is an important field of research, as it could allow chemist to prepare materials depicting multi-responsive properties. It is in this context that, pushed by a will to expand the chemical space of chalcogen-bonding interactions, a concept is put forward for which chalcogen- and halogen-bonding interactions can be used simultaneously to engineer multicomponent co-crystals. Through the rational design of crystallizable molecules, chalcogenazolo pyridine scaffold (CGP) modules were prepared that, bearing either a halogen-bond acceptor or donor at the 2-position, can interact with suitable complementary molecular modules undergoing formation of supramolecular polymers at the solid state. The recognition reliability of the CGP moiety to form chalcogen-bonded dimers allows the formation of heteromolecular supramolecular polymers through halogen-bonding interactions, as confirmed by single-crystal X-ray diffraction analysis.     

Photoinstability in active pharmaceutical ingredients: Crystal engineering as a mitigating measure

Cocrystallization has evolved as an attractive prospect to broaden the chemical landscape of a drug entity, expand its therapeutic scope, and address physicochemical deficiencies of an active pharmaceutical ingredient (API). The non-covalent approaches to address the solubility and bioavailability of BCS Class-II and Class-IV drugs is an archetypal example and is a prolific topic. The present review highlights various supramolecular methods employed in addressing the photoinstability in drugs, emphasizing crystal engineering approaches. Because a greater proportion of the drugs are formulated in the solid-state, the structural factors—crystal packing, intermolecular interactions, packing density—remain a critical determinant in the observed extent of stability. Comprehending and amending these structural determinants using crystal engineering concepts proposes to address the photoinstability in drugs. Also, we highlight the pros and cons of the different adopted strategies in terms of formulation and the underlying challenges and put in prospect. The review provides a correlative assessment of the structure-property relations that could further augment the foundations of factual knowledge in drug stability.     

Orthogonal multipolar interactions in structural chemistry and biology

The past few decades of molecular recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biological receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A number of illustrative examples of these interactions found in X-ray crystal structures of small molecules and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chemical and biological molecular recognition processes.     

Chalcogen Bonding: An Overview

In the last few decades, “unusual” noncovalent interactions like anion‐π and halogen bonding have emerged as interesting alternatives to the ubiquitous hydrogen bonding in many research areas. This is also true, to a somewhat lesser extent, for chalcogen bonding, the noncovalent interaction involving Lewis acidic chalcogen centers. Herein, we aim to provide an overview on the use of chalcogen bonding in crystal engineering and in solution, with a focus on the recent developments concerning intermolecular chalcogen bonding in solution‐phase applications. In the solid phase, chalcogen bonding has been used for the construction of nano‐sized structures and the self‐assembly of sophisticated self‐complementary arrays. In solution, until very recently applications mostly focused on intramolecular interactions which stabilized the conformation of intermediates or reagents. In the last few years, intermolecular chalcogen bonding has increasingly also been exploited in solution, most notably in anion recognition and transport as well as in organic synthesis and organocatalysis.     

Self-Assembly in Natural and Unnatural Systems

Although there are no fundamental factors hindering the development of nanoscale structures, there is a growing realization that “engineering down” approaches, in other words a reduction in the size of structures generated by lithographic techniques below the present lower limit of roughly 1 μm, may become impractical. It has, therefore, become increasingly clear that only by the development of a fundamental understanding of the self-assembly of large-scale biological structures, which exist and function at and beyond the nanoscale, downwards, and the extension of our knowledge regarding the chemical syntheses of small-scale structures upwards, can the gap between the promise and the reality of nanosystems be closed. This kind of construction of nanoscale structures and nanosystems represents the so-called “bottom up” or “engineering up” approach to device fabrication. Significant progress can be made in the development of nanoscience by transferring concepts found in the biological world into the chemical arena. Central to this mission is the development of simple chemical systems capable of instructing their own organization into large aggregates of molecules through their mutual recognition properties. The precise programming of these recognition events, and hence the correct assembly of the growing superstructure, relies on a fundamental understanding and the practical exploitation of non-covalent bonding interactions between and within molecules. The science of supramolecular chemistry—chemistry beyond the molecule in its very broadest sense—has started to bridge the yawning gap between molecular and macro-molecular structures. By utilizing inter-actions as diverse as aromatic π–π stacking and metal–ligand coordination for the information source for assembly processes, chemists have, in the last decade, begun to use biological concepts such as self-assembly to construct nanoscale structures and superstructures with a variety of forms and functions. Here, we provide a flavor of how self-assembly operates in natural systems and can be harnessed in unnatural ones.     

Programming Rapid Functional Group Diversification into a Solid-State Reaction: Aryl Nitriles for Self-Assembly,Click Reactivity,and Discovery of Coexisting Supramolecular Synthons

A method to rapidly diversify the molecules formed in organic crystals is introduced, with aryl nitriles playing a novel dual role as both hydrogen-bond acceptors and modifiable organic groups. The discovery of coexisting supramolecular synthons in the same crystal is also described. The general concept is demonstrated by using a bis(aryl nitrile) alkene that undergoes a hydrogen-bond-directed intermolecular [2+2] photodimerization to form a tetra(aryl nitrile)cyclobutane. The product is readily converted by click reactivity to a tetra(aryl tetrazole) and by hydrolysis to a tetra(aryl carboxylic acid). The integration of aryl nitriles into solid-state reactions opens broad avenues to post-modify products formed in crystalline solids for rapid diversification.     

Intra‐ and Intermolecular Dispersion Interactions in [n]Cycloparaphenylenes: Do They Influence Their Structural and Electronic Properties?

Cycloparaphenylenes (CPPs) are nanosized structures with unique isolated and bulk properties, and are synthetic targets for the template‐driven bottom‐up synthesis of carbon nanotubes. Thus, a systematic understanding of the supramolecular order at the nanoscale is of utmost relevance for molecular engineering. In this study, it is found that intramolecular noncovalent (dispersion) interactions must be taken into account for obtaining accurate estimates of the structural and optoelectronic properties of [n]CPP compounds, and their influence as the number of repeat units increases from n=4 to n=12 is also analyzed, both in the gas phase and in solution. The supramolecular self‐assembly, for which both intra‐ and intermolecular noncovalent interactions are relevant, of [6]CPP is also investigated by calculating the binding energies of dimers taken along several crystal directions. These are also used to estimate the cohesive energy of the crystal, which is compared to the value obtained by means of dispersion‐corrected DFT calculations using periodic boundary conditions. The reasonable agreement between both computational strategies points towards a first estimate of the [6]CPP cohesive energy of around 50 kcal mol^?1.     

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.     

Patterns in Hydrogen Bonding: Functionality and Graph Set Analysis in Crystals

Whereas much of organic chemistry has classically dealt with the preparation and study of the properties of individual molecules, an increasingly significant portion of the activity in chemical research involves understanding and utilizing the nature of the interactions between molecules. Two representative areas of this evolution are supramolecular chemistry and molecular recognition. The interactions between molecules are governed by intermolecular forces whose energetic and geometric properties are much less well understood than those of classical chemical bonds between atoms. Among the strongest of these interactions, however, are hydrogen bonds, whose directional properties are better understood on the local level (that is, for a single hydrogen bond) than many other types of non-bonded interactions. Nevertheless, the means by which to characterize, understand, and predict the consequences of many hydrogen bonds among molecules, and the resulting formation of molecular aggregates (on the microscopic scale) or crystals (on the macroscopic scale) has remained largely enigmatic. One of the most promising systematic approaches to resolving this enigma was initially developed by the late M. C. Etter, who applied graph theory to recognize, and then utilize, patterns of hydrogen bonding for the understanding and design of molecular crystals. In working with Etter's original ideas the power and potential utility of this approach on one hand, and on the other, the need to develop and extend the initial Etter formalism was generally recognized. It with that latter purpose that we originally undertook the present review.     

Supramolecular chemistry and crystal engineering

Supramolecular chemistry is the chemistry of molecular ensembles and intermolecular interactions. Currently it is a major, interdisciplinary branch of science dealing with chemical, physical, biological and technological aspects of the creation and study of complex chemical systems based upon non-valent interactions. Crystal engineering is a direction of supramolecular chemistry aimed at the design of periodic structures with a desired supramolecular organization. This paper shortly reviews the goals and research objects of supramolecular chemistry and crystal engineering and lists the most important historical facts and the literature.