Nierengarten Group


Covalent Chemistry

As part of our research directed towards the synthesis of complex nanomolecules that exhibit specific properties, we have recently extended our work on hexa-substituted fullerenes to scaffolds based on a pillar[5]arene core. Pillar[5]arenes are unique tubular-shaped macrocyclic compounds made of 1,4-disubstituted hydroquinone subunits linked by methylene bridges in their 2,5-positions. Before starting the development of functional systems, our first contribution in this field was related to a clear understanding of the reactions used for the preparation of these macrocyclic compounds. As far as their synthesis is concerned, pillar[n]arenes are usually prepared from 1,4-dialkoxybenzene derivatives and paraformaldehyde in the presence of a Lewis acid catalyst. We have shown that the cyclooligomerization is thermodynamically driven because of the reversibility of the Friedel-Crafts reaction, thus explaining the high yields in pillar[n]arenes and the preferential formation of cyclopentamers. This is an important finding and many recent developments in pillar[n]arene chemistry have been only possible based on our mechanistic investigations showing that dynamic covalent chemistry is at work.

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The reaction conditions typically used for the preparation of pillar[
n]arenes are not compatible with a large variety of functional groups and the direct synthesis of pillar[5]arenes bearing sophisticated substituents is often not possible. The cyclisation reaction is also sensitive to steric effects and the presence of large substituents on the starting 1,4-dialkoxybenzene considerably lowers the yields. This major problem was solved by producing readily accessible pillar[5]arene derivatives bearing 10 terminal groups allowing their further functionalization to generate structurally more complicated systems.

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Pillar[5]arene-Containing Rotaxanes

The development of new building blocks bearing complementary reactive groups with a controlled spatial repartition on the scaffold is a key step for the preparation of multifunctional molecules with unique properties. In this perspective, the existing pillar[5]arene scaffolds have some limitations. Indeed, whereas building blocks with 10 identical peripheral groups are conveniently prepared, pillar[5]arenes combining two different 1,4-dialkoxybenzene moieties is only possible under statistical conditions. Actually, a controlled synthesis appears difficult as cleavage of the Ar-CH2 bonds occurs under the Friedel-Crafts conditions used for their preparation and scrambling cannot be avoided. In order to overcome this problem, we became interested in taking profit of the capability of pillar[5]arenes to form host-guest complexes with alkyl chains to build rotaxane scaffolds. The macrocyclic pilar[5]arene component can carry ten copies of a first functional group, whereas the molecular axis of the rotaxane can be symmetrically or unsymmetrically substituted and thus carry one or two additional functional subunits. This prompted us to first investigate the reaction conditions for the preparation of [2]rotaxanes from pillar[5]arene building blocks. Pillar[5]arene-based [2]rotaxanes have been prepared from the reaction of diacyl chloride reagents with various amine stoppers. The yield in [2]rotaxane is sensitive to the reaction conditions (solvent, stoichiometry) but also to structural and electronic factors.

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Bioactive Pillar[5]arenes

The potential therapeutic applications of multivalent glycoclusters targeting bacterial adhesion lectins call for the design of core scaffolds presenting various valencies and topologies in order to understand the specificities of binding. Pillar[5]arenes are ideal candidates in this endeavor since they provide decavalent scaffolds on a minimal molecular architecture leading to dense presentation of carbohydrate epitopes on their periphery. The synthesis of pillar[5]arene-based glycoclusters was readily achieved by CuAAC conjugations from the azido- and alkyne-functionalized precursors. The binding properties of the glycosylated multivalent ligands were studied for different lectins.

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The synthetic approach combining recent concepts for the preparation of multifunctional nanomolecules (click chemistry on multifunctional scaffolds) with supramolecular chemistry (self-assembly to prepare rotaxanes) gave easy access to a large variety of sophisticated [2]rotaxane heteroglycoclusters. Specifically, compounds combining galactose and fucose have been prepared to target the two bacterial lectins (LecA and LecB) from the opportunistic pathogen
Pseudomonas aeruginosa.

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As part of this research on biologically active pillar[n]arene derivatives, we have also reported the preparation of polycationic dendritic pillar[5]arene derivatives and shown their capability of interacting with DNA. Owing to their efficient ability to compact DNA, these compounds have been used for gene transfer experiments thus opening new research avenues in the field of biological applications with pillar[n]arene derivatives.

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Nanoscopic Organization

A good understanding of the self-organization capabilities of pillar[n]arene derivatives is essential for many future applications. As part of this research, we have developed liquid-crystalline pillar[5]arene materials. Supramolecular lamellar organizations have been observed for liquid-crystalline pillar[5]arene derivatives with peripheral cyanobiphenyl subunits. In contrast, the functionalization of the pillar[5]arene core with Percec-type poly(benzylether) dendrons gave rise to the self-organization of tubular nanostructures within columnar phases.

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On the other hand, we have also shown that the design of amphiphilic pillar[5]arene-containing [2]rotaxanes is an efficient strategy to obtain compounds with a perfect hydrophilic/hydrophobic balance allowing the formation of stable Langmuir films. The size of the peripheral alkyl chain of the pillar[5]arene subunit plays an important role on the reversibility during compression-decompression cycles and gliding motions in these mechanically interlocked molecules influence their packing within the thin films.

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