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Fundamentals of ASymmeTric Organo-CATalysis

Periodic Reporting for period 2 - FASTO-CAT (Fundamentals of ASymmeTric Organo-CATalysis)

Reporting period: 2018-10-01 to 2020-03-31

Organo-catalysis, which uses purely organic molecules to catalyze chemical conversions, is a very promising route to avoid the use of potentially toxic transition metals in catalysis. Despite the broad applicability of organo-catalysts to a variety of chemical reactions, the fundamentals on the interaction of the catalysts with reactants in solution have remained elusive. Within this project we elucidate these fundamentals, like e.g. binding strength, binding lifetime, binding geometry, etc. with the aim of providing generic structure-function relationships to guide the design of new catalyses. Such relationships help transitioning the optimization of catalytic cycles and design of new catalytic routes from currently largely trial-and-error based approaches towards a rational design.
Within this project we focus on three well established binding motifs of organo-catalysts: thiourea, diol, and phosphoric acids, which all have been shown to provide superior catalytic activity and also allow for control of the mirror-symmetry of the catalyzed reactions (i.e. stereocontrol). For these catalysts the project aims at (i) elucidating the nature of the catalyst-substrate bonds, (ii) correlating the binding parameters to catalytic conversion, (iii) determining structure-function relationships between molecular geometries and catalytic efficiencies, and (iv) exploring the molecular-level origins of stereocontrol. Within the first 2.5 years of the project we have focused on objectives (i) and (ii).
For the diol catalysts we could show that for two isomeric catalysts, the catalyst forms a single, extremely long-lived, hydrogen-bond to the substrate molecule. Remarkably, comparison of the two isomeric catalysts showed that the number of catalysts that bind to substrate does not correlate to stereocontrol. Rather, better stereocontrol is achieved with a rigid catalyst, for which only a few catalysts interact with the substrate, yet, with a well-defined binding geometry.
For the phosphoric acid based catalysts we could show that interaction is dominated by very strong doubly ionic hydrogen-bonds, which make the catalyst-substrate bond very flexible. Unexpectedly, we could show that molecular aggregates consisting of one reactant and multiple phosphoric acid molecules are formed at conditions used in our experiments. These results help understanding previous controversies on the interaction nature and so far little understood effects of solvents on catalyst substrate binding. Moreover, for catalyses where such dual activation is essential, our results provide routes to choose the ideal experimental conditions.
For thiourea based catalysts, we found that interaction with reactants is very weak under catalytically relevant conditions, making it challenging to detect molecular binding in solution. However, substitution with electron-withdrawing trifluoromethyl groups can markedly enhance the interaction. Thus, our results indicate that even very weak binding to reactants can give rise to good catalytic conversion and appropriate modifications of the catalysts can enhance reactivity even further.
Until the end of the project it is envisioned that the bonding dynamics of the catalysts to the substrate are elucidated in greater detail and that we will obtain size-function relationships for the studied catalysts.

For the phosphoric acid catalysts our current results suggest that the bonding dynamics occur on timescales much faster than typical reaction rates of a catalytic conversion. Hence, our findings suggest that the intermolecular bonds can nearly instantaneously adopt to changes nuclear distances during chemical conversion, which may be the key towards the wide applicability of these catalysts. Until the end of the project we will elucidate how these flexible bonds are affected by the symmetry (chirality) of the catalyst and the substrate.

Conversely, for the diol and thiourea catalysts we found rather slow bonding dynamics. Until the end of the project we will elucidate how the nature and size of the substrate affects these dynamics and how different substrates affect the angular degree of freedom of the substrate in such bonded intermediates. For the thiourea catalysts we will focus on trifluoromethyl substituted catalysts, as these exhibit a sufficient number of intermolecularly bonded intermediates. Eventually these bonding parameters will be correlated to catalytic efficiency in order to determine the key ingredients for effective stereocontrol.
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