![[img]](https://epub.uni-regensburg.de/style/images/fileicons/application_pdf.png) | License: Publishing license for publications excluding print on demand (28MB) |
- URN to cite this document:
- urn:nbn:de:bvb:355-epub-535743
- DOI to cite this document:
- 10.5283/epub.53574
| Item type: | Thesis of the University of Regensburg (PhD) |
|---|---|
| Open Access Type: | Primary Publication |
| Date: | 20 February 2023 |
| Referee: | Prof. Dr. Ruth M. Gschwind |
| Date of exam: | 13 December 2022 |
| Institutions: | Chemistry and Pharmacy > Institut für Organische Chemie > Arbeitskreis Prof. Dr. Ruth Gschwind |
| Keywords: | NMR-spectroscopy; NMR; organocatalysis; Brønsted acid catalysis; chiral phosphoric acid |
| Dewey Decimal Classification: | 500 Science > 540 Chemistry & allied sciences |
| Status: | Published |
| Refereed: | Yes, this version has been refereed |
| Created at the University of Regensburg: | Yes |
| Item ID: | 53574 |
Abstract (English)
Catalysis with Brønsted acids is a long-lasting success story and was realized in the field of (asymmetric) organocatalysis by combining an acidic motif with a chiral organic framework consisting of a backbone as source of chirality and substituents to shape a stereoinductive environment. Modulation of the acidic motif, backbone and substituents allowed to adapt these chiral Brønsted acids to a ...
Abstract (English)
Catalysis with Brønsted acids is a long-lasting success story and was realized in the field of (asymmetric) organocatalysis by combining an acidic motif with a chiral organic framework consisting of a backbone as source of chirality and substituents to shape a stereoinductive environment. Modulation of the acidic motif, backbone and substituents allowed to adapt these chiral Brønsted acids to a myriad of different transformations and challenges. However, this adaptability also makes a sophisticated and rational catalyst design crucial. General design principles rely on detailed insights into the reaction mechanism and a good understanding of possible reaction pathways and parameters. Therefore, in this thesis chiral phosphoric acids (CPA) were exemplarily selected as catalyst class and studied regarding their mode and degree of activation, structural space and confinement, secondary non-covalent interactions decisive for stereoselectivity, association and aggregation of catalyst and reactants and different general reac-tion pathways.
The structural space of CPA/substrate intermediates was elucidated in the third chapter of this thesis on the example of the transfer hydrogenation of imines with Hantzsch ester as hydride source. For the binary CPA/imine complexes, four general core structures (Type I E, Type II E, Type I Z and Type II Z) were found which are anchored by a strong hydrogen bond. These complexes feature either the E- or Z-imine in each two conformations (rotation of the imine by ~180°). The structures of the complexes are highly conserved over a range of different 3,3’-substituents of the CPA and different substituents of the imine. Additionally, for the first time [CPA/imine]2 dimers of the binary CPA/imine complexes were ob-served in solution and identified via characteristic highfield shifts and Diffusion Ordered Spectroscopy (DOSY) NMR measurements. These [CPA/imine]2 dimers are expected not to affect the reaction as they resemble an off-cycle equilibrium with the monomeric CPA/imine complexes.
The equilibrium between the different imine conformations (Type I and Type II) for the CPA/E-imine intermediates was studied in the fourth chapter of this thesis. The exchange between Type I E and Type II E is fast on the NMR time scale but could be accessed by adapting the Relaxation Dispersion R1 NMR method for the first time to an organocatalytic system. This method allowed to extend the time-frame of observable dynamic processes from the millisecond to the microsecond (nanosecond with additional low temperature) time scale. Different exchange pathways were found featuring either switching of the PO----H-N+ hydrogen bond from one oxygen atom of the phosphoric acid to the other one or switching and rotation of the imine inside the binding pocket of the CPA. The exchange rate of the switching process was found to depend on the hydrogen bond strength of the CPA/imine intermedi-ate, allowing a faster switching process for weaker hydrogen bonds. Moreover, the rotation of the imine inside the binding pocket was found to be only possible for smaller CPA or imine substituents. Additionally, measurements at different temperatures allowed to not only access the exchange rates but even the populations of the Type I E and Type II E conformations. Based on this, the equilibrium between these two conformations was investigated as a molecular balance system for quantification of weak London dispersion interactions between CPA and imine. The CPA/imine complex structures were shown to be conserved for imines with bulky dispersion energy donor (DED) substituents such as iso-propyl and tert-butyl groups and the exchange process between the Type I E and Type II E confor-mations could in principle be accessed by the R1 NMR method. However, the interaction energy be-tween DED substituent and CPA could not be clearly dissected, as the DED substituent was shown to affect both the Type I E and Type II E structure either through a direct interaction or its substituent ef-fect even for CPAs with 3,3’-substituents as small as a phenyl group.
An alternative reaction pathway featuring hydrogen bond bridged CPA dimers was studied in the fifth chapter of this thesis on the example of the two-fold transfer hydrogenation of quinolines. A strong dependence of the enantioselectivity on the catalyst loading was observed and kinetic measurements revealed a catalyst order of 1.25 to 1.75 depending on the catalyst concentration. Low temperature NMR measurements at a 2:1 ratio of catalyst and quinoline substrate confirmed the presence of dimer-ic CPA/CPA/quinoline intermediates and were confirmed by DOSY NMR measurements. Additionally, CPA/CPA/imine complexes were also found, indicating the potential impact of the dimeric reaction channel for this substrate class. Compared to the monomeric CPA/imine complexes, the CPA/CPA/imine dimers feature a stronger proton transfer onto the substrate (weaker PO----H-N+ hydrogen bond) and their formation was found to be strongly dependent on the 3,3’-substituent of the catalyst and less on the imine substituents. Applying the Relaxation Dispersion R1 NMR method, the presence of a fast exchange process was revealed which indicates the presence of at least two fast exchanging CPA/CPA/E-imine conformers.
CPA/imine intermediates with imines featuring an additional hydroxy group as hydrogen bond donor were studied in the sixth chapter of this thesis. In contrast to the previous assumption that a bidentate binding of catalyst and imine by two hydrogen bonds results in a well-defined reaction intermediate, a broad structural space was found for these CPA/imine systems. Different dimer species were found as dominant species for most systems and characterized via DOSY NMR. In these dimers, two imine mole-cules form each one hydrogen bond to two different CPA molecules, effectively bridging them. Molecu-lar dynamic simulations revealed different bridging motifs and it is suggested that these bridged dimers can act as an alternative reaction pathway. Fine-tuning of steric and electrostatic properties of CPA and imine allowed to access monomeric CPA/imine dimers and the bidentate binding motif was clearly vali-dated. NOESY NMR revealed the structure of these intermediates, in which the imine is placed in be-tween the two 3,3’-substituents of the CPA. One 3,3’-substituent is shielding one site of the imine which confirms the postulated origin of stereoselectivity for the following transformations.
The seventh and eighth chapter of this thesis were done in collaboration with Franziska Pecho from the group of Prof. Dr. Thorsten Bach and focused on merging Brønsted acid catalysis with photocatalysis. A chiral phosphoric acid was used as organocatalysts and thioxanthone unites were implemented as 3,3’-substituents which served as light-harvesting photosensitizer. In the asymmetric [2+2] photocycloaddi-tion of β-carboxyl-substituted cyclic enones, binding of the carboxylic acid substrate to the CPA catalyst was proven by low temperature NMR studies via NOESY and DOSY NMR experiments. Temperature coefficients for the chemical shift of the hydrogen bonded proton signals were derived by variable tem-perature NMR experiments and revealed the presence of monomeric and dimeric/oligomeric CPA/substrate species. In the asymmetric [2+2] photocycloaddition of cyclic N,O-acetals, the genera-tion of an open iminium ion form was validated upon protonation of the cyclic N,O-acetal and biden-tate binding by two hydrogen bonds of the resulting imine substrate to the CPA was proven. The CPA/imine intermediate was characterized as hydrogen bond assisted ion pair and two different sub-strate conformations were identified, differing in the arrangement of the substrate backbone. Addi-tionally, NMR kinetic measurements during illumination with visible light showed that during the reac-tion isomerization of the C=C or C=N double bond of the substrate is possible. These isomerization pro-cesses can in principle affect the reaction, changing the environment for the addition step (if the C=N double bond is isomerized) or lead to a different diastereomer of the product (if the C=C double bond is isomerized).
The secondary non-covalent interactions decisive for the enantioselectivities in CPA catalyzed trans-formations were studied in the ninth chapter of this thesis, resulting in a conceptual approach on ex-ploiting London dispersion interactions to systematically enhance stereoselectivities. For the CPA cata-lyzed transfer hydrogenation of (E)- or (Z)-N-phenyl ketimines, tert-butyl groups as dispersion energy donors (DED) were placed in all meta-positions of the substrate, which lead to a stabilization of the Z-imine by up to 4.5 kJ/mol. For the free imines, the equilibrium between low populated Z-imine (~1%) and major populated E-imine (~99%) was accessed by Chemical Exchange Saturation Transfer (CEST) NMR. The effect of stabilizing the Z-imine by DED residues was proven to be transferred onto the binary CPA/imine and ternary CPA/imine/Hantzsch ester intermediates, leading to a thermodynamic prefer-ence of the Z-intermediates. For the enantioselectivities, a clear correlation between London dispersion stabilization and enantioselectivity was found, allowing to convert moderate-good to good-excellent enantioselectivities under dispersion control and exceeding the typical enantiomeric ratios for standard imine substrates.
Translation of the abstract (German)
Im Rahmen dieser Arbeit wurden mechanistische Untersuchungen mittels NMR-Spektroskopie im Bereich der Brønstedsäurekatalyse mit chiralen Phosphorsäuren durchgeführt. Dabei wurde der Strukturraum von Intermediaten, dynamische Prozesse und Aggegration und Dimerisierung sowie die Rolle von London Dispersionswechselwirkungen genauer untersucht.
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