Periodic Reporting for period 4 - FASTO-CAT (Fundamentals of ASymmeTric Organo-CATalysis)
Periodo di rendicontazione: 2021-10-01 al 2022-09-30
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.
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.