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Fundamentals of ASymmeTric Organo-CATalysis

Periodic Reporting for period 4 - FASTO-CAT (Fundamentals of ASymmeTric Organo-CATalysis)

Reporting period: 2021-10-01 to 2022-09-30

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 project we installed and validated a time-resolved infrared spectroscopy lab. From these validation experiments separate publications on the dynamics of water and electrolyte solutions emerged.
Studies of the interactions and dynamics of catalysts with representative substrates showed that the interaction motifs in solution are very rich and there is nothing like a single reactive intermediate for a catalyst binding to a substrate. Moreover, our results showed that binding strengths of molecular complexes in solution can be rather weak. The multitude of reactive intermediates together with the weak binding strength required development of combined experimental approaches to elucidate such weak binding.
For the phosphoric acid catalysts we found that not only catalyst-substrate complexes form in solution, but also reactive intermediates consisting of more than one phosphoric acid molecule. These multimeric aggregates are sensitive to the solvent environment and can as such explain the sensitivity of the catalytic activity to the solvent conditions. The interaction of reactive substrate with more than one phosphoric acid moiety has meanwhile been shown to be a powerful design route towards tailoring the catalytic pathway. Our findings further showed that such multimeric reactive intermediates open efficient pathways for dissipating excess energy from the catalytic center. We also found that, rather than the initially anticipated steric factors influencing binding strength, the electronic structure of the substrate markedly affects interaction with the catalysts.
For the diol catalysts our findings suggest that instead of the commonly inferred binding strength, the conformational rigidity of the catalyst is pivotal for the catalytic activity: Comparison of weakly active catalysts to a highly active isomeric from suggested that mostly the conformational rigidity correlates with the catalytic conversion efficiency. Within this project we further developed a methodology to extract hydrogen-bond strength distributions from experimental vibrational spectroscopic information, aided by spectroscopic computations.
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. Substitution with electron-withdrawing trifluoromethyl groups can markedly enhance the interaction. Our experiments also allowed for extracting the different catalyst geometries in solution and demonstrated that, trifluoromethyl substitution not only affects the electronic structure of the catalysts, but also shifts conformational equilibria. Some of these conformations sterically restrict access to the active center of the catalyst, explaining the largely varying catalytic activities. Access to the catalysts active site can further be restricted via interaction motifs, other than the hydrogen-bond donor site of the catalyst and the hydrogen-bond acceptor site at the substrate.
Overall, our results demonstrate that – at conditions relevant to catalysis – a multitude of interaction sites and, hence, reactive intermediates exist. Tuning these interactions independently can help optimizing existing and designing new catalytic routes. These results have been made available to the scientific community via – to date 19 - openly accessible scientific publications and also disseminated via presentations at international conferences.
In the course of the project we addressed the general challenge to quantify weak interaction of solutes in liquids. Therefore, we developed experimental approaches based on different experimental observables to reliably determine such weak interactions. These methods also allowed for determining conformational equilibria in solutions, which has been challenging at catalytically relevant conditions. Due to the high complexity of the interaction motifs in solution, we also outlined an experimental route towards isolating hydrogen-bond strength distributions from vibrational spectroscopies, which can impact other research fields for which hydrogen-bonding interactions are pivotal. As such, our results will be highly relevant to interaction of solutes with hydrogen-bonded liquids, such as water.
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