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Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ChalEnz (Catalysis with Chalcogen Bonds: Toward Artificial Enzymes)

Teaser

Advances in science and technology come from the discovery of new and conceptually innovative ways to control the interactions and behaviour of matter and to extract new functions and applications from them. In this regard, exotic non-covalent interactions such as chalcogen...

Summary

Advances in science and technology come from the discovery of new and conceptually innovative ways to control the interactions and behaviour of matter and to extract new functions and applications from them. In this regard, exotic non-covalent interactions such as chalcogen bonds, from the attraction of negative sites to a chalcogen atom, and anion-pi, from the stabilization of anions on electron-deficient aromatic units, have been barely explored and their implementation in functional systems should result in a breakthrough in current science, amplifying the repertoire of supramolecular interactions available up to date.

The main objective of this project is the development of these unorthodox interactions as a tool in oganocatalysis and enzymatic catalysis, controlling the stabilization of reactive intermediates and transition states and modulating the outcome of the chemical transformation.

From here, two different goals are presented:

- Design of new molecular scaffolds able to interact with anions and negatively-charged reactive species through chalcogen bonds and study their performance as catalysts. Implementation of these systems in artificial enzymes would be highly desirable, with the idea of having access to asymmetric catalysis, on one hand, and of introducing this novel interaction in biological systems, on the other hand.

- Amplify the number of molecular scaffolds that shows activity in anion-pi catalysis. So far, small napthalenediimides (NDIs) and related structures have been the only players able to perform efficiently in anion-pi catalysis. Thus, the discovery of other materials that could increase the rather small collection of catalysts, such as electron-deficient fullerenes and/or other carbon allotropes, would result in a tremendous evolution of this research area.


Conclusions:

- Different molecules have been tested in chalcogen bonding catalysis, bearing a common central structure, dithienothiophene, decorated with different electron-withdrawing groups to increase the acidity of the sigma-hole, responsible of the interaction between the chalcogen atom with electron-rich units. Several of these structures have showed good catalytic activity in chemical transformations, with perfect correlation between the strength of the sigma-hole and the performance as catalysts (Figure 1). However, the implementation of this structures in artificial enzymes did not succeed. Chalcogen bonding interactions are not strong enough to activate the substrate in very polar solvents, i.e. water.

- Regading anion-pi catalysis, fullerenes and other carbon allotropes have been implemented in the portfolio of organic materials able to perform with this unconventional type of catalysis (Figure 2 and figure 4). In-depth study has been performed during this action, both related to the optimization of the chemical structure of the catalyst and the understanding of the parameters that govern anion-pi interactions with carbon nanomaterials. From this, a new direction in anion-pi catalysis has emerged, where highly polarizable materials rather than small and very electron-deficient ones reveal very good stabilization of anions and negatively-charged reactive intermediates and, thus, high activity as catalysts (Figure 3).

Work performed

1. Design and synthesis of new catalysts bearing a dithienothiophene central core and electron-withdrawing groups to increase acidity of the sigma-holes of the central sulfur atoms.
- Different aryl and alkyl imides, nitrile groups, sulfone...
- Compounds show good anion binding observed by fluorescence titrations using organic solvents.
2. Test of the catalysts in chemical reactions: quinoline and isoquinoline reduction using Hantzch ester as hydride source.
- Compounds show catalytic activity in organic polar solvents such as dichloromethane.
3. Synthesis of different cofactors bearing the chalcogen-bonding scaffold coupled to a biotin residue, to place the catalyst inside the chiral pocket of Streptavidin (Chalcogen-bonding artificial enzyme).
4. Attempt to find chemical transformations where the chalcogen-bonding enzyme could be applied:
- Transfer hydrogenation, epoxide opening, bromide abstraction
- Reactions only worked in organic solvents at relatively high concentration of catalysts (no ideal conditions for enzymatic catalysis).

5. Design and synthesis of fullerene derivatives bearing a tertiary amine to be used in anion-pi catalysis using a model reaction (Malonic acid half thioester addition to nitroolefins).
- Tertiary amine is located through different linkers and with different space lengths. Tuning of LUMO energy level of fullerene accomplished by changing nature of substituents in the cyclopropane (hydrogen, nitrile)
6. Test of fullerenes in the chemical transformation.
- Best results obtained with the tertiary amine in close proximity to the aromatic surface. Demonstration of anion-pi interactions.
7. Further optimization of catalysts by remote control of their polarizability and electron-density
- Introduction of a second fullerene unit or other electron-deficient aromatic structures able to increase polarizability of the system and to remove electron density by partial charge transfer.
- Best results in catalysis for those systems with increased polarizability rather than increased acidity. New direction in anion-pi interactions.
8. Introduction of other carbon allotropes in anion-pi catalysis
- Single-walled and multi-walled carbon nanotubes, graphene and graphene quantum dots are being tested as organocatalysts using anion-pi interactions.

All results have been widely shared in both academic and non-academic environments by different media:
- Scientific papers in top-qualified journals: JACS, ACIE
- Posters and presentations in different national and international conferences: ISMSC 2018 (Canada), GRC 2017 (Switzerland) and NCCR meetings at national level (6 in 2 years)
- Press releases at local and national level.

Final results

The biggest breakthrough accomplished during the evolution of this action has been the discovery of the activity of carbon nanomaterials as catalyst working through anion-pi interactions. This discovery came together with the demonstration of the importance of polarizability to stabilize anions on top of the big aromatic surface of these structures. In fact, best results are yet to come using carbon nanotubes and graphene in anion-pi catalysis. In this last particular project, I have been directly involved in its coordination and management, supervising at the same time a PhD student in the group of Prof. Matile, the host research group of this action. The results will be submitted to a high impact factor journal very soon.

Although, a priori, these results only represent an interesting discovery from a fundamental point of view, given the relevance and prospective applications of carbon nanostructures, in particular carbon nanotubes and graphene, in our society in the near future, we expect that our results will add an extra value to these materials and that new interesting applications will emerge.

Website & more info

More info: https://www.unige.ch/sciences/chiorg/matile/.