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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - GLYCONHC (Exploiting carbohydrate/N-heterocyclic carbene hybrid complexes as innovative multifunctional oxidation catalysts with tailoring of weak interactions allowing for development of enzyme mimics)

Teaser

Summary

There is a constant need to improve and streamline catalytic reactions which can transform pharmaceutically-relevant functional groups (e.g. alcohols, amines, ketones, aldehydes). Taking advantage of naturally-occurring carbohydrates (sugars) in the design of new catalysts offers many opportunities to tune their properties. This project combines the beneficial properties of carbohydrates (water solubility, well-defined stereochemistry and recognition) with triazolylidene N-heterocyclic carbenes to provide for synergistic catalysis.

NHCs are synthetically versatile and have been demonstrated to have beneficial properties as ligands for catalysis. Triazolylidene NHCs are accessible via modular \'click\' chemistry and readily functionalised, but not as widely explored as other classes of related compounds. Functionalising carbenes with carbohydrates is practically unknown in the literature despite many advantages such derivatives would possess, including well-defined geometry, rich hydrogen bonding and proton-shuffling interactions, recognition by biological receptors (providing the opportunity for probing interactions between catalysts and proteins) and also chirality (allowing for enantioselectivity).

The key objective of this project is the development of innovative hybrid complexes for catalysis of pharmaceutically relevant functional groups, by combining the beneficial properties of triazolylidene N-heterocyclic carbenes and carbohydrates for synergistic catalysis. A range of novel carbohydrate-functionalised NHC complexes (with Ru(II) and Ir(III)) were synthesised for these purposes and relationships between carbohydrate structure/geometry/linkage and catalytic activity probed.

Work performed

From a range of structurally-diverse carbohydrate and glycoside azides, three distinct families of new carbohydrate-functionalised triazolium salts were prepared, as precursors to triazolylidene N-heterocyclic carbene ligands. Ruthenium-triazolylidene complexes were synthesised and characterised by numerous techniques (spectroscopic, electrochemical, elemental analysis). Catalytic activity was probed for a number of oxidative and reductive transformations. Acetyl-protected carbohydrate-NHC hybrid complexes were deprotected in situ and efficiently performed transfer hydrogenation on a range of ketone substrates. A manuscript describing these results is being prepared for publication.

Control experiments for oxidative catalytic coupling of amines, revealed the unprecedent ability of certain triazolium salts to catalyse this reaction selectively. This catalytic system was probed and a publication on the activity of triazolium salts will be forthcoming.

Iridium-NHC complexes were prepared from functionalization of various carbohydrates with the triazolylidene motif. Catalytic activity of these complexes for direct hydrogenation of ketones and aldehydes under mild aqueous conditions and low hydrogen pressure was determined. Activity was pH-dependent, and unprotected carbohydrate systems out-performed acetyl-protected analogues. These iridium complexes were compatible with physiological media, such as aqueous buffer solutions. Through collaboration with Prof F. Paradisi (Nottingham, UK), the ability of carbohydrate-functionalised Iridium-complexes to interact with glycoside hydrolase was probed. A manuscript on the synthesis, properties and catalytic activity of these iridium complexes is being prepared for publication.

These, and related, iridium-complexes were also employed as catalysts for oxidative dehydrogenation of carbohydrates through a collaboration with Prof J. Mata (CastellÃ³n, ES). A publication describing these results is being prepared for publication.

This work has been disseminated chiefly through attendance at conferences, participation in CaRLa Catalysis Winter School (Germany), presenting posters (6) at conferences in Switzerland, Ireland, Netherlands, oral presentation at a major conference (International Conference on Coordination Chemistry in Japan) and at the Catalysis Winter School. Social media (Twitter, LinkedIn, blog) has been used in conjunction with attendance at conferences to share contents of presentations with a wider audience, in addition to explaining the project to visiting researchers, school students and members of the public who visit the Department of Chemistry as part of open days or outreach activities. 4-5 articles are expected to be published in the near future based on results from this project.

Final results

Despite the many advantages carbohydrates can confer on catalytic systems, only a handful of examples of carbohydrate-modified NHC complexes are reported. This project has expanded the scope of this field, demonstrating the first use of unprotected carbohydrate-NHC complexes in reductive catalysis: both transfer hydrogenation with Ru (through in situ deprotection), and direct hydrogenation under mild aqueous conditions with Ir. Specific triazolium salts were also discovered to have excellent activity for selective oxidative coupling of amines, and the mechanism of this reaction has been investigated. This reactivity was not previously known, and may provide an economical strategy for the production of imines, a class of molecules which are relevant to, for example, synthesis of pharmaceutical molecules.

Unprotected Ir-carbohydrate-NHC hybrid complexes had good catalytic activity in physiologically relevant media, including buffer solutions at various pH values. Presence of protecting groups on carbohydrate alcohol groups retarded the catalytic activity for ketone hydrogenation, indicating the importance of solubility and possibly bifunctionality in catalysis. The compatibility with biological media allowed probing of interactions with a carbohydrate-recognising protein.

This project determined conclusively the relationships between carbohydrate structure and asymmetry in iridium-catalysed ketone hydrogenation reactions providing guidelines for developing the next generation of hybrid catalysts in order to tune higher enantioselectivity.