Hydrogen bonds are crucial for various processes of life. Mimicking nature, generations of chemists have used hydrogen bonds in many fields of chemistry, including catalysis. Parallel to simple activation, the catalyst may also create a special spatial environment around the substrate and may thus direct the attack of other molecules. This is particularly important in the synthesis of chiral molecules, i.e. molecules which exist in two mirror-image forms, so-called enantiomers. Often, the two enantiomers have very different biological and pharmaceutical effects: while one molecule may act as a very potent pharmaceutical, its mirror-image may cause severe side effects. Thus, there is a high demand for methods which allow the enantioselective synthesis of just one mirror-image version of a chiral molecule, especially in the pharmaceutical industry. At the moment however, the only noncovalent (weak) interaction used for this purpose is hydrogen bonding. Alternative interactions would open up new exciting possibilities for synthesis, as new substrates might become accessible for catalysis.
A relatively little known alternative to hydrogen bonds are halogen bonds, which are based on the interaction of a positively polarized halogen atom with electron-rich compounds. Since the 1990s, halogen bonding has been established as a powerful means to direct the assembly of molecules in the solid state and in crystalline material. In solution, the interaction is still scarcely investigated and interest in these kinds of studies has only really emerged since about 2005. In that last few years, several groups, including ours, have shown that halogen bonding may be used in noncovalent organocatalysis. None of the presently known examples, however, deals with enantioselective organocatalysis as described above. Next to halogens, chalcogen atoms also form related interactions (chalcogen bonds), which are scarcely explored. For instance, there is no precedence for the application of chalcogen bonding in organocatalysis.
In this project, we strive to establish halogen bonding and chalcogen bonding as reliable tools in organocatalysis. With halogen bonding, the focus will be on enantiodiscriminating processes, i.e. in the selective synthesis or recognition of one mirror-image version of a molecule. To this end, we will synthesize suitable chiral (asymmetric) halogen bonding molecules as catalyst candidates and will screen their efficiency by carefully chosen test reactions. Our approach will be based on polyfluorinated compounds or on cationic ones, and the synthesis of appropriate catalyst structures will be the decisive basis for all further studies. In the mid- and long-term, our focus will shift from simple catalysts with one binding site to multidentate ones which can bind to substrates by multiple interactions. As test reactions, we will pursue two parallel routes: reactions in which the substrate is split up into two charged parts (cation and anion) by action of the catalyst, and reactions in which neutral organic molecules are activated. Chalcogen bonds are far less explored and thus our efforts with this interaction will concentrate on fundamental proof-of-principle studies.
