The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.

The Halogen Bond

The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

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Mechanochemistry: opportunities for new and cleaner synthesis

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: A Holistic View

How do molecules aggregate in solution, and how do these aggregates consolidate themselves in crystals? What is the relationship between the structure of a molecule and the structure of the crystal it forms? Why do some molecules adopt more than one crystal structure? Why do some crystal structures contain solvent? How does one design a crystal structure with a specified topology of molecules, or a specified coordination of molecules and/or ions, or with a specified property? What are the relationships between crystal structures and properties for molecular crystals? These are some of the questions that are being addressed today by the crystal engineering community, a group that draws from the larger communities of organic, inorganic, and physical chemists, crystallographers, and solid state scientists. This Perspective provides a brief historical introduction to crystal engineering itself and an assessment of the importance and utility of the supramolecular synthon, which is one of the most important concepts in the practical use and implementation of crystal design. It also provides a look to the future from the viewpoint of the author, and indicates some directions in which this field might be moving.

Crystal engineering: from molecule to crystal.

Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?

Getting the right balance between intermolecular interactions is crucial for the synthesis of supermolecules in a preconceived manner. The three-component supermolecule in the ternary cocrystal of 3,5-dinitrobenzoic acid, isonicotinamide, and 4-(dimethylamino)benzoic acid (1:1:1) assembles through a "primary" (between the stronger acid and pyridine) and a "secondary" hydrogen-bonding interaction (between the weaker acid and amide).

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1521-3773%2820010903%2940%3A17%3C3240%3A%3AAID-ANIE3240%3E3.0.CO%3B2-X

“Total Synthesis” Supramolecular Style: Design and Hydrogen-Bond-Directed Assembly of Ternary Supermolecules

The X-ray crystal structure determinations of twelve cocrystals involving iso-nicotinamide and a variety of carboxylic acids have revealed a very consistent pattern of hydrogen-bond preferences. The combination of a monocarboxylic acid, an amide, and a pyridine moiety leads, in every case, to discrete “supermolecules” (consisting of two molecules of iso-nicotinamide and two molecules of the relevant carboxylic acid) with well-defined and robust connectivity. The two dominant (regularly occurring) supramolecular synthons in these crystal structures are (1) the heteromeric carboxylic acid···pyridine hydrogen bond and (2) a self-complementary amide···amide hydrogen-bond interaction, both of which prevail in the presence of widely differing chemical functionalities. In four of these cocrystals, a dicarboxylic acid is employed, which alters the structural outcome from discrete entities to infinite assemblies (or to a hexameric complex in a “U-shaped” dicarboxylic acid), which is fully expected since the two pr...

A high-yielding supramolecular reaction.

Combining halogen bonds and hydrogen bonds in the modular assembly of heteromeric infinite 1-D chains

The combination of isonicotinamide with AgBF4 or AgClO4, respectively, led to isostructural compounds [tris(isonicotinamide)silver(I) tetrafluoroborate and tris(isonicotinamide)silver(I) perchlorate], containing two 3-D interpenetrating nets of three-co-ordinate silver(I) ions linked by N–H· · ·O hydrogen bonds between adjacent isonicotinamide ligands.

Two-fold interpenetration of 3-D nets assembled via three-co-ordinate silver(I) ions and amide–amide hydrogen bonds

The crystal structure of 4-nitrobenzamide pyrazinecarboxamide (1 ∶ 1) contains two homomeric amide⋯amide dimers, which is in sharp contrast with the structural motifs displayed by the vast majority of binary co-crystals (illustrated here with five new examples), where the driving force for the supramolecular assembly is one or more strong heteromeric intermolecular interactions.

Brian A. Helfrich

Papers

“Total Synthesis” Supramolecular Style: Design and Hydrogen-Bond-Directed Assembly of Ternary Supermolecules

A high-yielding supramolecular reaction.

Combining halogen bonds and hydrogen bonds in the modular assembly of heteromeric infinite 1-D chains

Two-fold interpenetration of 3-D nets assembled via three-co-ordinate silver(I) ions and amide–amide hydrogen bonds

Heteromeric intermolecular interactions as synthetic tools for the formation of binary co-crystals