Periodic Reporting for period 4 - XBCBCAT (From Supramolecular Chemistry to Organocatalysis: Fundamental Studies on the Use of Little-Explored Non-Covalent Interactions in Organic Synthesis)
Période du rapport: 2019-11-01 au 2020-04-30
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.
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.
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. After extensive development, we now have methods in hand to prepare variously substituted multidentate chiral neutral halogen bond donors, with chiral moieties attached at different positions of the core structures. Their application in enantioselective reactions has been tested in the latter part of the project, and these experiments continue. 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. A series of co-crystallization studies have been performed, but so far no resolution of racemates could be realized.
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. In the second part of the project, we have moved to bidentate versions and have successfully completed the synthesis of two catalyst classes. One of these catalysts has achieved the first enantioselective reaction in which asymmetric induction was solely based on halogen bonding. In addition, related compounds could also be employed for chiral recognition.
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. Several types of compounds are now available, and all of them have been successfully used as organocatalysts. These studies include the first use of organoselenium compounds as intermolecular Lewis acids in organocatalysis, the first catalytic such use, and the first use of dicationic Tellurium-based organocatalysts. The latter, in particular, have been proven to be very active in the activation of a nitro derivative.
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. In the second part of the project, we have moved to bidentate versions and have successfully completed the synthesis of two catalyst classes. One of these catalysts has achieved the first enantioselective reaction in which asymmetric induction was solely based on halogen bonding. In addition, related compounds could also be employed for chiral recognition.
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. Several types of compounds are now available, and all of them have been successfully used as organocatalysts. These studies include the first use of organoselenium compounds as intermolecular Lewis acids in organocatalysis, the first catalytic such use, and the first use of dicationic Tellurium-based organocatalysts. The latter, in particular, have been proven to be very active in the activation of a nitro derivative.
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.
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.