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

Halogen Bonding in Supramolecular Chemistry.

Applications of Supramolecular Anion Recognition

Halogen bonding is an emerging noncovalent interaction for constructing supramolecular assemblies. Though similar to the more familiar hydrogen bonding, four primary differences between these two interactions make halogen bonding a unique tool for molecular recognition and the design of functional materials. First, halogen bonds tend to be much more directional than (single) hydrogen bonds. Second, the interaction strength scales with the polarizability of the bond-donor atom, a feature that researchers can tune through single-atom mutation. In addition, halogen bonds are hydrophobic whereas hydrogen bonds are hydrophilic. Lastly, the size of the bond-donor atom (halogen) is significantly larger than hydrogen. As a result, halogen bonding provides supramolecular chemists with design tools that cannot be easily met with other types of noncovalent interactions and opens up unprecedented possibilities in the design of smart functional materials.This Account highlights the recent advances in the design of hal...

The halogen bond in the design of functional supramolecular materials: recent advances.

The research on 1,2,3-triazoles has been lively and ever-growing since its stimulation by the advent of click chemistry The attractiveness of 1H-1,2,3-triazoles and their derivatives originates from their unique combination of facile accessibility via click chemistry and truly diverse supramolecular interactions, which enabled myriads of applications in supramolecular and coordination chemistry The nitrogen-rich triazole features a highly polarized carbon atom allowing the complexation of anions by hydrogen and halogen bonding or, in the case of the triazolium salts, via charge-assisted hydrogen and halogen bonds On the other hand, the triazole offers several N-coordination modes including coordination via anionic and cationic nitrogen donors of triazolate and triazolium ions, respectively After CH-deprotonation of the triazole and the triazolium, powerful carbanionic and mesoionic carbene donors, respectively, are available The latter coordination mode even features non-innocent ligand behavior Moreover, these supramolecular interactions can be combined, eg, in ion-pair recognition, preorganization by intramolecular hydrogen bond donation and acceptance, and in bimetallic complexes Ultimately, by clicking two building blocks into place, the triazole emerges as a most versatile functional unit allowing very successful applications, eg, in anion recognition, catalysis, and photochemistry, thus going far beyond the original purpose of click chemistry It is the intention of this review to provide a detailed analysis of the various supramolecular interactions of triazoles in comparison to established functional units, which may serve as guidelines for further applications

Beyond click chemistry - supramolecular interactions of 1,2,3-triazoles.

Over the last 15 years, hydrogen-bond donors, such as thiourea derivatives, have been used as noncovalent organocatalysts with ever-increasing sophistication. Yet, despite the large structural variety of the currently known noncovalent organocatalysts, virtually all are based on the same interacting atom: positively polarized hydrogen. Although it has been known for a long time that compounds featuring electrophilic halogen substituents also form adducts with Lewis bases, the corresponding interaction (“halogen bonding”) 4] was mostly ignored until the 1990s. An important difference between these two noncovalent interactions is the invariably high directionality of halogen bonds, with R X LB angles that are close to 1808 (X = Cl,Br,I; LB = Lewis base). Most studies involving halogen bonds are related to the solid state and to crystal engineering, but in recent years an increasing number of applications in solution-phase have been published, including fundamental studies and reports on anion receptors. In organocatalysis, the involvement of halogen bonds has only been postulated in two cases. Bolm et al. reported that iodoperfluoroalkanes catalyze the reduction of quinoline derivatives. The participation of halogen bonds in this reaction was derived from experimental observations. In a second example, iodine trichloride was reported to catalyze the ring-opening polymerization of l-lactide. The elucidation of the exact mode of action of this highly reactive interhalogen compound is not trivial, though, and in both reported cases the analysis is further complicated by the possible presence of traces of acid. One particular application of hydrogen-bonding organocatalysts is based on the coordination to anions and/or the abstraction of the latter from organic substrates (“anion binding mechanism”). Recently, we could show that halogen-bond donors may also serve as activators in a halide-abstraction benchmark reaction. To date, however, only dicationic compounds (based on either imidazolium, pyridinium, or 1,2,3-triazolium backbones) proved to be active, and stoichiometric amounts of the halogen-bond donor needed to be employed. As the use of cationic compounds comes along with several limitations (for example, concerning solubility, synthetic accessibility, and the presence of counteranions), our next goal was to design neutral halogen-bond donors for use as activators or, ideally, organocatalysts. At present, our studies have primarily proof-of-principle character to demonstrate the feasibility of halogen-bondbased organocatalysis. In the long term, we envision that halogen-based organocatalysts and hydrogen-bond donors will complement each other. Halogen-bond donors might be especially suitable for Lewis basic substrates featuring heavier elements (such as sulfur, phosphorous, or the halogens) or for certain reaction conditions. Furthermore, neutral fluorinated halogen-bond donors will likely allow the use of very nonpolar or fluorinated solvents in organocatalysis. Finally, the high directionality of halogen bonds might prove advantageous in future halogen-bond-catalyzed enantioselective transformations. In analogy to thiourea organocatalyst 1, we strove to develop multidentate halogen-based Lewis acids without further functional groups to study the isolated effect of halogen bonding. The 2,6-diiodo-3,4,5-trifluorophenyl group (Scheme 1) was chosen as building block for several reasons,

Organocatalysis by Neutral Multidentate Halogen-Bond Donors†

Halogen‐Bond‐Induced Activation of a Carbon–Heteroatom Bond

Activation of a carbonyl compound by halogen bonding.

We have conducted isothermal calorimetric titrations to investigate the halogen-bond strength of cationic bidentate halogen-bond donors toward halides, using bis(iodoimidazolium) compounds as probes. These data are intended to aid the rational design of halogen-bond donors as well as the development of halogen-bond-based applications in solution. In all cases examined, the entropic contribution to the overall free energy of binding was found to be very important. The binding affinities showed little dependency on the weakly coordinating counteranions of the halogen-bond donors but became slightly stronger with higher temperatures. We also found a marked influence of different solvents on the interaction strength. The highest binding constant detected in this study was 3.3 × 106 M–1.

Sebastian M. Walter

Papers

Organocatalysis by Neutral Multidentate Halogen-Bond Donors†

Halogen‐Bond‐Induced Activation of a Carbon–Heteroatom Bond

Activation of a carbonyl compound by halogen bonding.

Isothermal calorimetric titrations on charge-assisted halogen bonds: role of entropy, counterions, solvent, and temperature.

5-Iodo-1,2,3-triazolium-based multidentate halogen-bond donors as activating reagents