Dr. Charlotte Gers-Panther, Associate Editor European Journal of Organic Chemistry, talked to Professor Jean-François Nierengarten, Université de Strasbourg, France, about his work on the solvent-free preparation of pillar[5]arene‐containing [2]rotaxanes that was recently published in European Journal of Organic Chemistry.

 

 

Professor Nierengarten, you have explored a mechanochemical approach for the synthesis of pillar[5]arene‐containing [2]rotaxanes. What was the inspiration behind this study?

In recent years, we have started a research program on the development of easy to functionalize molecular scaffolds. These building blocks are used for the preparation of complex molecular systems showing specific properties for applications in biology and materials science. The availability of these compounds is a critical aspect for their applicability and an important challenge is to find new orthogonal strategies allowing to increase the molecular complexity without being limited by the synthetic route.

In this respect, we became interested in combining the concepts we have developed for the preparation of multifunctional systems with supramolecular chemistry. Specifically, we started to prepare pillar[5]arene-based rotaxane scaffolds. This was the driving-force to investigate new strategies for the preparation of [2]rotaxanes. As the yields for the synthesis of rotaxanes in solution are often limited by many factors, we had to explore new strategies and thus started to use mechanochemistry for their preparation.

 

 

Mechanochemical reactions have become increasingly popular. Why did you choose this technique?

The preparation of mechanically interlocked molecules such as rotaxanes requires the pre-organization of molecular components in appropriate supramolecular ensembles. In the particular case of pillar[5]arene-based systems, the stability of the key supramolecular intermediate, the pseudo-rotaxane, is rather weak in solution. As a result, the yields in rotaxanes are not always satisfactory. We became thus interested in using mechanochemical solvent-free conditions anticipating that dissociation of the pseudo-rotaxane will be limited in the solid state. It worked out extremely well.

 

 

What is the broader impact of this paper for the scientific community?

It is always difficult to anticipate the impact of a specific paper. We hope that our work will contribute to popularizing solvent-free mechanochemistry in the field of supramolecular chemistry and that our methodology will be useful to other research groups.

In a more general context, chemists will play a central role in solving some of the major environmental issues of our modern society. We have to think about chemistry in a different way to produce the chemicals we need in a sustainable way without producing wastes. I believe that solvent-free mechanochemistry has a bright future in this perspective.

 

 

Which part of your work proved the most challenging?

We bought the mixer mill unit for this specific project. In the beginning, our main problems were related to technical issues due to our lack of experience in the field of mechanochemistry. My co-worker, Michel Holler, did a great job with a team of three highly motivated undergraduate students, Timothée Stoerkler, Alexandra Louis and Fanny Fisher. They quickly learned how to master our new tool.

For the preparation of the rotaxanes, the most challenging part was to obtain solid-state samples of the inclusion complex to form the desired rotaxane derivatives in good yields.

 

 

How will you follow up on this discovery?

There is still a lot of room to improve the preparation of mechanically interlocked molecules under solvent-free conditions and the scope of this method has still to be investigated in details. For the moment, we have limited our studies on amide bond formation. We would like to find other suitable reactions to prepare different series of pillar[5]arene-based rotaxanes and thus to introduce a larger structural diversity. This is important for all our studies connected to the design of pillar[5]arene-based rotaxane scaffolds.

On the other hand, we would like to also apply our mechanochemical approach to other macrocyclic compounds such as cyclodextrins and calixarenes. The preparation of rotaxanes in high yields is often challenging and there is a clear need for simple new procedures allowing the large-scale synthesis of such compounds.

 

 

This year marks the 50th birthday of rotaxanes since they were first reported in 1969 by Schill and Zollenkopf. Which aspect of rotaxanes do you find most fascinating?

In a way, I became a chemist because of my fascination for mechanically interlocked molecules in general and rotaxanes in particular. I was actually studying biology and biochemistry at the University of Strasbourg and switched my graduate studies to inorganic chemistry for the last year of my Master’s degree after I met Jean-Pierre Sauvage. I discovered the beautiful molecules prepared in his team while reading a highlight on the first synthesis of a molecular knot in a popular scientific journal. This prompted me to visit Jean-Pierre as I was looking for a research team in which to do my traineeship. After more than one hour of a memorable scientific discussion, I was fully convinced to join his group to work on mechanically interlocked molecules and thus I became a chemist.

When I started my independent research in 1996, I developed a research program on fullerene chemistry. While focusing on other topics, I was always following the literature on mechanically interlocked molecules. When we extended our work from fullerene scaffolds to pillar[5]arene building blocks, the development of rotaxane scaffolds was an obvious choice.

More then twenty years after my Ph.D., it is a great pleasure to work again in this field but with a completely different perspective. My fascination for mechanically interlocked molecules is still the same: To find appropriate solutions to prepare them is a stimulating intellectual challenge. Behind their esthetically appealing molecular structures, the possibility of controlling the intramolecular motions in rotaxanes to prepare functional molecular machines is another fascinating aspect of this particular field.

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The article they talked about

• Mechanochemical Solvent‐Free Conditions for the Synthesis of Pillar[5]arene‐Containing [2]Rotaxanes,
  Michel Holler, Timothée Stoerkler, Alexandra Louis, Fanny Fischer, Jean‐François Nierengarte,
  Eur. J. Org. Chem. 2019.
  https://doi.org/10.1002/ejoc.201900153