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Mechanical Chirality: Synthesis, Properties and Applications at a New Horizon in Supramolecular Stereochemistry

Periodic Reporting for period 4 - MechaniChiral (Mechanical Chirality: Synthesis, Properties and Applications at a New Horizon in Supramolecular Stereochemistry)

Reporting period: 2021-10-01 to 2022-09-30

Molecular chirality, the ability for molecules to exist in two mirror image forms in the same way that left and right hands do, is a central theme in chemistry; each year >10% of publications in leading chemistry journals concerned chirality. Chirality can arise due to several different structural features and all of those studied so far have found applications throughout the sub-disciplines of chemistry including as catalysts, materials and sensors.

Mechanically chiral rotaxanes are molecules in which the threading of a linear dumbbell shaped component through a ring shaped component leads to the appearance of chirality, as opposed to the structure of the ring or dumbbell components themselves. These unusual molecules represent a novel and unexplored class of chiral molecules. However, the lack of a scalable methods for their isolation has prevented all but the most cursory investigation of their properties. Thus, mechanical chirality remains an unexplored frontier in chemistry with the potential to deliver novel functions and impact across a range of chemical disciplines from materials chemistry to the synthesis of pharmaceutically active compounds.

Within the period of this ERC Consolidator Grant, Prof Stephen Goldup led a team to investigate the synthesis, properties and applications of these intriguing mechanically chiral molecules. The key conclusions of the study were:

1. It is possible to make mechanically chiral molecules in high stereopurity using auxiliary methods.

2. Through their synthetic investigations, the team identified several new forms of mechanical stereochemistry that had lain unnoticed for over half a century and provided a systematic framework for their discussion and assignment.

3.The first examples of mechanically chiral molecules with applications in enantioselective catalysis were demonstrated, suggesting that mechanical stereochemistry has a role to play in solving synthetic problems of relevance across chemistry and biology.

4.Chiral sensors for small molecules were developed based on co-conformational stereochemistry and these are now being extended to systems that do not rely on circular dichroism.

5. Mechanically chiral metal-based luminophores were developed and their photophysical properties are now under investigation.

6. It is possible to model the chiroptical properties of mechanically chiral molecules, raising the possibility of assigning their absolute stereochemistry more readily in future.
During the project the MechaniChiral team achieved the following key scientific breakthroughs:

1) New, general scalable methods to make mechanically chiral rotaxanes

We have developed new chemical techniques that allow us to make new types of mechanically chiral molecules, including mechanically planar chiral, mechanically axially chiral and mechanical geometric isomers. These methods have opened up the structures whose properties and applications can be investigated. These methods are exceptionally flexible, in one case, allowing 11 new mechanically chiral molecules to be made using simple starting materials. Although we focused primarily on synthetic routes using the active template approach, towards the end of the project we also observed stereoselectivity in other systems that we will exploit in future.

2) Mechanically chiral sensors

We have developed mechanically chiral rotaxanes that interact with other small molecules to provide information about the purity of samples and their properties. Having demonstrated this principle we are now developing practical examples that can be used in the development of new chemical reactions and the analysis of medically relevant samples.

3) Mechanically chiral catalysts

We have demonstrated the first examples of catalysts based on mechanically chiral molecules. With prototypes in hand, we are now investigating the benefits of this new approach to catalyst development. We also discovered new ways of controlling catalyst activity using the mechanical bond, which open new paths for exploiting catenanes and rotaxanes in future.

4) Unexpected findings

During our work on MechaniChiral, we also discovered new types of stereochemistry and clarified long-held misconceptions, both of which place the field of mechanostereochemistry on a firmer theoretical footing. We also re-discovered some key effects of the mechanical bond on coordination chemistry, which we are now exploiting in the development of single ion magnets and ligands for medical imaging.

We are exploiting our results in various ways, from extending our studies on catalysis and sensing towards practically useful systems, to developing new types of prodrugs and imaging agents in collaboration with new project partners.

Our results have been widely disseminated through scientific publications (28 to date with several more in preparation/under consideration), including key review articles that provide a detailed explanation of our stereochemical findings and analysis. Prof Goldup and his team have delivered lectures all over the world at scientific meetings and university colloquia describing the findings of the project, including public, keynote and award lectures.
During the project we have taken mechanically chiral molecules from being inaccessible chemical curiosities to accessible molecules for practical investigations. We have also, for the first time, fully delineated the forms of stereochemistry that rotaxanes and catenanes can display, providing a firmer theoretical footing for the field to develop upon. Using our techniques, we have demonstrated exciting new applications of chiral rotaxanes and catenanes, providing evidence that such molecules have a part to play in solving real-world chemical problems.
Image of chiral rotaxanes and catenanes