Crystal engineering

Crystal engineering is the design and synthesis of molecular solid state structures with desired properties, based on an understanding and use of intermolecular interactions. The two main strategies currently in use for crystal engineering are based on hydrogen bonding and coordination bonding. These may be understood with key concepts such as the supramolecular synthon and the secondary building unit. Crystal engineering is the design and synthesis of molecular solid state structures with desired properties, based on an understanding and use of intermolecular interactions. The two main strategies currently in use for crystal engineering are based on hydrogen bonding and coordination bonding. These may be understood with key concepts such as the supramolecular synthon and the secondary building unit. The term 'crystal engineering' was first used in 1971 by Gerhard Schmidt in connection with photodimerization reactions in crystalline cinnamic acids. Since this initial use, the meaning of the term has broadened considerably to include many aspects of solid state supramolecular chemistry. A useful modern definition is that provided by Gautam Desiraju, who in 1988 defined crystal engineering as 'the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the design of new solids with desired physical and chemical properties.' Since many of the bulk properties of molecular materials are dictated by the manner in which the molecules are ordered in the solid state, it is clear that an ability to control this ordering would afford control over these properties. Crystal engineering relies on noncovalent bonding to achieve the organization of molecules and ions in the solid state. Much of the initial work on purely organic systems focused on the use of hydrogen bonds, though with the recent extension to inorganic systems, the coordination bond has also emerged as a powerful tool. In addition to this, especially through studies during the last decade, the use of halogen bonds has proved beneficial in providing additional control in crystal design. Other intermolecular forces such as π...π and Au...Au interactions have all been exploited in crystal engineering studies, and ionic interactions can also be important. However, the two most common strategies in crystal engineering still employ only hydrogen bonds and coordination bonds. Molecular self-assembly is at the heart of crystal engineering, and it typically involves an interaction between complementary hydrogen bonding faces or a metal and a ligand. By analogy with the retrosynthetic approach to organic synthesis, Desiraju coined the term 'supramolecular synthon' to describe building blocks that are common to many structures and hence can be used to order specific groups in the solid state. The carboxylic acid dimer represents a simple supramolecular synthon, though in practice this is only observed in approximately 30% of crystal structures in which it is theoretically possible. The Cambridge Structural Database (CSD) provides an excellent tool for assessing the efficiency of particular synthons. The supramolecular synthon approach has been successfully applied in the synthesis of one dimensional tapes, two dimensional sheets and three dimensional structures. The CSD today contains atomic positional parameters for nearly 800 000 crystal structures, and this forms the basis for heuristic or synthon based or 'experimental' crystal engineering. A major development in the field of crystal engineering in the last decade is related to the development of design strategies for bi-component and higher multi-component crystals (also known as cocrystals). The design of cocrystals is a difficult task as it involves recognition between different molecules which might be completely different in shape and size. Therefore, the more the number of components in a crystal, the more challenging it is to synthesize. Initially, the synthesis of cocrystals was centered on the design of binary ones. This is most often achieved with strong heteromolecular interactions. Ternary ones were designed mainly by interaction insulation, interaction hierarchy or by shape-size mimicry. However, it has been shown recently that it is possible to synthesize up to five-component crystals by choosing a suitable retrosynthetic strategy. The main relevance of multi-component crystals, apart from the synthetic challenge, arises from the advantage of tuning a particular property by changing the components. The main development in this front is focused upon designing pharmaceutical cocrystals. Pharmaceutical cocrystals are generally composed of one API (Active Pharmaceutical Ingredient) with other molecular substances that are considered safe according to the guidelines provided by WHO (World Health Organization). It has been shown that various properties (such as solubility, bioavailability, permeability) of an API can be modulated through the formation of pharmaceutical cocrystals. The study and formation of 2D architectures (i.e., molecularly thick architectures) has rapidly emerged as a branch of engineering with molecules. The formation (often referred as molecular self-assembly depending on its deposition process) of such architectures lies in the use of solid interfaces to create adsorbed monolayers. Such monolayers may feature spatial crystallinity in an investigated time window, and thus the terminology of 2D crystal engineering is well suited. However the dynamic and wide range of monolayer morphologies ranging from amorphous to network structures have made of the term (2D) supramolecular engineering a more accurate term. Specifically, supramolecular engineering refers to '(The) design (of) molecular units in such way that a predictable structure is obtained' or as 'the design, synthesis and self-assembly of well defined molecular modules into tailor-made supramolecular architectures'. The field of 2D crystal engineering has advanced over the years especially through the advent of scanning probe microscopic techniques which enable one to visualize networks with sub-molecular precision. Understanding the mechanism of these two dimensional assemblies may provide insights to the bottom up fabrication processes at the interfaces. The many aspects of developments in this field include the understanding of interactions, studies on polymorphism, design of nanoporous networks. Engineering the size and symmetry of the cavities and performing host guest chemistry inside the pores under nano confinement remains an attractive interest of this field. More recently, multicomponent networks are also studied that are formed by the application of crystal engineering principles. Although, there is a very high influence of the underlying substrate on the formation of the two dimensional assemblies, at least in a few cases, a relation was found between 2D assemblies and the bulk crystal structures. Polymorphism is the phenomenon wherein the same chemical compound exists in different crystal forms. In the initial days of crystal engineering, polymorphism was not properly understood and incompletely studied. Today, it is one of the most exciting branches of the subject partly because polymorphic forms of drugs may be entitled to independent patent protection if they show new and improved properties over the known crystal forms. With the growing importance of generic drugs, the importance of crystal engineering to the pharmaceutical industry is expected to grow exponentially.