The halogen bond is an attractive interaction in which an electrophilic halogen atom approaches a negatively polarized species. Short halogen atom contacts in crystals have been known for around 50 years. Such contacts are found in two varieties: type I, which is symmetrical, and type II, which is bent. Both are influenced by geometric and chemical considerations. Our research group has been using halogen atom interactions as design elements in crystal engineering, for nearly 30 years. These interactions include halogen···halogen interactions (X···X) and halogen···heteroatom interactions (X···B). Many X···X and almost all X···B contacts can be classified as halogen bonds. In this Account, we illustrate examples of crystal engineering where one can build up from previous knowledge with a focus that is provided by the modern definition of the halogen bond. We also comment on the similarities and differences between halogen bonds and hydrogen bonds. These interactions are similar because the protagonist atoms-halogen and hydrogen-are both electrophilic in nature. The interactions are distinctive because the size of a halogen atom is of consequence when compared with the atomic sizes of, for example, C, N, and O, unlike that of a hydrogen atom. Conclusions may be drawn pertaining to the nature of X···X interactions from the Cambridge Structural Database (CSD). There is a clear geometric and chemical distinction between type I and type II, with only type II being halogen bonds. Cl/Br isostructurality is explained based on a geometric model. In parallel, experimental studies on 3,4-dichlorophenol and its congeners shed light on the nature of halogen···halogen interactions and reveal the chemical difference between Cl and Br. Variable temperature studies also show differences between type I and type II contacts. In terms of crystal design, halogen bonds offer a unique opportunity in the strength, atom size and interaction gradation; this may be used in the design of ternary cocrystals. Structural modularity in which an entire crystal structure is defined as a combination of modules is rationalized on the basis of the intermediate strength of a halogen bond. The specific directionality of the halogen bond makes it a good tool to achieve orthogonality in molecular crystals. Mechanical properties can be tuned systematically by varying these orthogonally oriented halogen···halogen interactions. In a further development, halogen bonds are shown to play a systematic role in organization of LSAMs (long range synthon aufbau module), which are bigger structural units containing multiple synthons. With a formal definition in place, this may be the right time to look at differences between halogen bonds and hydrogen bonds and exploit them in more subtle ways in crystal engineering.
The preference of Br to form type II contacts over type I is explored by various techniques. The mechanical properties of some dihalogenated phenols are correlated with their structures.
Co-crystals of 4,4'-bipyridine and 4-hydroxybenzoic acid (1 : 2) show synthon polymorphism with the former being more stable. A 2 : 1 co-crystal is pseudopolymorphic within the same structural landscape with the structural roles of the two bipyridine N-atoms being distinct, as evidenced by mimicry by 4-phenylpyridine.
2- and 5-methylresorcinol form co-crystals with 4,4'-bipyridine in which some of the bipyridine molecules are loosely bound. These molecules can be replaced with other molecules of a similar shape and size to give a general method for the engineering of a ternary co-crystal.
It has been 20 years since the concept of supramolecular synthon was introduced with the purpose of rational supramolecular synthesis. While this concept has been greatly successful in employing a retrosynthetic approach in crystal engineering, the past few years have seen a continuous evolution of supramolecular synthons from being a synthetic subunit to a basic unit for understanding the dynamics of crystallization. This review attempts to give a glimpse of such developments.C rystal engineering is defined as "the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties". 1 If crystals are supramolecular equivalents of molecules, crystal engineering is a supramolecular equivalent of organic synthesis. In this sense, the aim in crystal engineering is to correlate molecular structures with crystal structures.However, finding an empirical model to establish such correlation was difficult. Despite some remarkable efforts made in early 1970s 2 (mainly by changing molecular substitution and observing the effect in resulting crystal structures), a general model was absent. Crystallization, which is often considered as a supramolecular reaction, follows the Curtin−Hammet principle which states that the population of the final products is largely dictated by the energy barrier of formation rather than relative enthalpic differences ( Figure 5). 3 Hence, it is more likely to observe kinetic (metastable) products instead of the thermodynamic one in any crystallization. Therefore, any model based completely on close packing (geometrical model), as proposed by Kitaigorodskii, 4 would fail to propose a realistic structure in most cases. Adopting a model completely based on the interaction hierarchy (i.e., chemical model) is also not viable as close packing forces usually play a deciding role in the final stages of crystallization. In reality, many structures are dictated by both chemical as well as geometrical models in a complex convoluted way. This could be a reason why crystal structures are most often considered as emergent properties (lacking a direct correlation with the functional groups present in the respective molecular structures). 5 To be more precise, understanding this dichotomy between geometrical and chemical models in the formation of crystal structures constitutes the central problem of crystal engineering.To this end, and to predict crystal structures from molecular structures, a model was required that took into account the components of both the geometrical and the chemical models. In this context, and drawing an analogy with the synthon from molecular chemistry, the concept of the supramolecular synthon was introduced. "Supramolecular synthons are structural units within supermolecules which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions." 6 In a direct sense, the concept of supramolecular synthons...
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