Improbable folded macrocycle shapes through interactional frustration

• Applicant: Professor Dr. Ivan Huc
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496492331

Controlling molecular shape is essential to the design of molecular function. Accessing to new molecular shapes thus paves the way to new properties. Both folding and macrocyclization are established approaches to the stabilization of molecular shape, but they generally produce probable shapes, that is, shapes that are within the reach of the unfolded or acyclic precursors in the sense that they are not enthalpically or entropically disfavored. Following the recent publication of key preliminary results, this project aims at developing two new strategies that combine folding and macrocyclization to generate improbable molecular shapes. In the first strategy, a molecular backbone with a strong folding propensity will be prevented from folding the way it prefers, i.e. frustrated, through macrocyclization. For that purpose, folding disruptors will be introduced to allow for macrocyclization to take place and removed afterwards. In the second strategy, dynamic covalent macrocycles, i.e. macrocycles whose units can reversibly recombine, will be equipped with functionalities that can promote non covalent interactions in such a way that these cannot be fulfilled in the small rings so that large (up to 23 units!), entropically disfavored, macrocyles are generated that possess well defined folded shapes. Both strategies thus exploit the orchestration of some form of frustration of non-covalent interactions. They are also based on related building blocks involving aromatic and peptidic units. The obtained improbable molecular shapes will be investigated, along with their molecular recognition properties and their ability to transmit conformational strain to molecular functions inserted in the backbones.

• DFG Programme: Research Grants