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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - XBCBCAT (From Supramolecular Chemistry to Organocatalysis: Fundamental Studies on the Use of Little-Explored Non-Covalent Interactions in Organic Synthesis)

Teaser

Summary

Hydrogen bonds are ubiquitous in nature. They are crucial for various processes of life and they also allow for the specific binding of substrates in enzyme pockets. The noncovalent interaction of molecules by hydrogen bonding is based on the attraction between a positively polarized hydrogen atom on one molecule and an electron-rich atom on the second molecule. Mimicking nature, generations of chemists have used hydrogen bonds in many fields of chemistry, e.g. to orient molecules in solid state structures. A further very important application of hydrogen bonds is in the context of catalysis. By coordination of a hydrogen bonding catalyst to a substrate, the latter is activated and the reaction to the aspired product is facilitated. Parallel to this activation, the catalyst may also create a special spatial environment around the substrate and may thus direct the attack of other molecules, e.g. by blocking one side of the substrate. This is particularly important in the synthesis of chiral molecules, i.e. molecules which exist in two mirror-image forms, the 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 substrates which are not coordinated or activated very well by hydrogen bonding might become accessible for catalysis. In addition, the selectivity of the catalyst, i.e. the preferred binding of one substrate over the other, might change substantially. This might enable the synthesis of products which are currently difficult to prepare.
Interestingly, alternative interactions similar to hydrogen bonding do exist, even if they are still relatively unknown. The most prominent of these are halogen bonds, which are based on the interaction of a positively polarized halogen atom (instead of the hydrogen atom in hydrogen bonding), with electron-rich compounds. One everyday example of this attraction is the color of elemental iodine in different solvents: while iodine is purple in solvents like pentane, its color changes to brown-orange in water, indicating an interaction between the compound and the solvent. Effects like these have been known for almost 200 years but only few detailed investigations had been performed until the 1990s (with few isolated exceptions). Since then, halogen bonding has been established as a powerful means to direct the assembly of molecules in the solid state and in crystalline material, e.g. in the preparation of organic semiconductors or liquid crystals. 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 similar to the well-known hydrogen bonding based catalysts. None of the presently known examples, however, deals with enantioselective organocatalysis as described above (i.e., the synthesis of just one mirror-image variant of a molecule). Next to halogens, chalcogen atoms like selenium and tellurium may also form weak interactions with electron-rich parts of other molecules. The corresponding noncovalent interactions have been called â€œchalcogen bondingâ€ and it features many similarities with hydrogen and especially halogen bonding. In contrast to the latter, it has still been much less explored and there are only isolated examples of its use in the synthesis of solid state materials. Similarly, there is no precedence for the application of chalcogen b

Work performed

A strong focus on the experimental work in the first half of this project has been on the synthesis of suitable halogen and chalcogen bonding molecules for the various applications aspired. One subproject was directed at the synthesis of chiral (asymmetric) fluorinated catalyst candidates. Here we had to develop and optimize novel synthetic routes towards the preparation of the core structure of such compounds. Various reaction conditions were screened and several hundred test reactions were performed in order to establish a reliable protocol for the synthesis of highly fluorinated and iodinated catalysts. We have found ideal reaction conditions for the construction of such molecules and the synthesis of first examples of neutral asymmetric halogen bonding molecules is completed. Additionally, we have also succeeded in the preparation of related neutral halogen bonding molecules which feature divergent binding sites. This approach is based on the modification of known asymmetric core structures with halogen-substituted rests. The compounds shall then be employed for enantiodiscriminating processes, and first screening experiments are underway. Parallel to this, we have also started several projects to design and prepare cationic halogen bonding molecules. The target structures are based on those core structures which have proven effective in simple test reactions before. Asymmetry (chirality) is introduced by suitable rests bound to these backbones. In this first phase of the project, our attention was mainly directed at compounds that are able to establish one halogen bond to the corresponding substrate. Lately, we have moved on to analogues with multiple binding sites. With the currently available catalyst candidates, we have started to screen benchmark reactions and the initial results look promising. In the subproject dealing with activation by chalcogen bonding, we have established synthetic routes toward the preparation of cationic catalyst candidates which possess two binding sites for substrates. In order to realize a rational design and optimization of potential catalysts, we have synthesized a range of different compounds in which several structural factors are systematically varied. The compounds have been successfully used in a benchmark reaction for carbon-halogen bond activation in a stoichiometric fashion and have also been successfully employed in a first proof-of-principle case as organocatalysts.

Final results

Currently, only very few chiral (asymmetric) halogen bonding molecules are available and none of these look promising for applications in catalysis. In the first half of this project, we establish suitable chiral halogen bonding molecules for further test reactions and screenings. This is an important basis for the development of halogen bonding based applications in organic chemistry and beyond. In parallel, we also establish chalcogen bond donors as activators and organocatalyst in suitable test reactions. Prior to this project, the use of chalcogen bonding in organocatalysis was unprecedented, so the introduction of a further interaction into this field creates many additional fascinating options for catalyst design.
The only directional noncovalent interaction used in (enantioselective) organocatalysis at the moment is hydrogen bonding. The inclusion of novel interactions as further tools in this field would likely enable much better adaption of the catalyst structure to the needs of the substrates: while some substrates may be ideally fit for hydrogen bonding, others might be better suited for activation by halogen bonding or chalcogen bonding. Consequently, we expect that underexplored interactions like halogen and chalcogen bonding will become important for a range of substrates and will be the basis of various future enantioselective transformations. This will allow the synthesis of compounds which are currently either not accessible or very difficult to obtain. Since the pharmaceutical industry is in high demand of chiral molecules, the potential impact in this and other fields is considerable.