Bidentate Substrate Binding in Brønsted Acid Catalysis: Structural Space, Hydrogen Bonding and Dimerization

BINOL derived chiral phosphoric acids (CPAs) are a prominent class of catalysts in the field of asymmetric organocatalysis, capable of transforming a wide selection of substrates with high stereoselectivities. Exploiting the Brønsted acidic and basic dual functionality of CPAs, substrates with both a hydrogen bond acceptor and donor functionality are frequently used as the resulting bidentate binding via two hydrogen bonds is expected to strongly confine the possible structural space and thus yield high stereoselectivities. Despite the huge success of CPAs and the popularity of a bidentate binding motif, experimental insights into their organization and origin of stereoinduction are scarce. Therefore, in this work the structural space and hydrogen bonding of CPAs and N-(ortho-hydroxyaryl) imines (19 CPA/imine combinations) was elucidated by low temperature NMR studies and corroborated by computations. The postulated bidentate binding of catalyst and substrate by two hydrogen bonds was experimentally validated by detection of trans-hydrogen bond scalar couplings. Counterintuitively, the resulting CPA/imine complexes showed a broad potential structural space and a strong preference towards the formation of [CPA/imine]2 dimers. Molecular dynamics simulations showed that in these dimers, the imines form each one hydrogen bond to two CPA molecules, effectively bridging them. By finetuning steric repulsion and noncovalent interactions, rigid and well-defined CPA/imine monomers could be obtained. NOESY studies corroborated by theoretical calculations revealed the structure of that complex, in which the imine is located in between the 3,3’-substituents of the catalyst and one site of the substrate is shielded by the catalyst, pinpointing the origin or stereoselectivity for downstream transformations

A Structural Diversity of Molecular Alkaline‐Earth‐Metal Polyphosphides: From Supramolecular Wheel to Zintl Ion

A series of molecular group 2 polyphosphides has been synthesized by using air‐stable [Cp*Fe(η(5)‐P(5))] (Cp*=C(5)Me(5)) or white phosphorus as polyphosphorus precursors. Different types of group 2 reagents such as organo‐magnesium, mono‐valent magnesium, and molecular calcium hydride complexes have been investigated to activate these polyphosphorus sources. The organo‐magnesium complex [((Dipp)BDI−Mg(CH(3)))(2)] ((Dipp)BDI={[2,6‐( i )Pr(2)C(6)H(3)NCMe](2)CH}(−)) reacts with [Cp*Fe(η(5)‐P(5))] to give an unprecedented Mg/Fe‐supramolecular wheel. Kinetically controlled activation of [Cp*Fe(η(5)‐P(5))] by different mono‐valent magnesium complexes allowed the isolation of Mg‐coordinated formally mono‐ and di‐reduced products of [Cp*Fe(η(5)‐P(5))]. To obtain the first examples of molecular calcium‐polyphosphides, a molecular calcium hydride complex was used to reduce the aromatic cyclo‐P(5) ring of [Cp*Fe(η(5)‐P(5))]. The Ca‐Fe‐polyphosphide is also characterized by quantum chemical calculations and compared with the corresponding Mg complex. Moreover, a calcium coordinated Zintl ion (P(7))(3−) was obtained by molecular calcium hydride mediated P(4) reduction

PACS - Realization of an adaptive concept using pressure actuated cellular structures

A biologically inspired concept is investigated which can be utilized to develop energy efficient, lightweight and applicational flexible adaptive structures. Building a real life morphing unit is an ambitious task as the numerous works in the particular field show. Summarizing fundamental demands and barriers regarding shape changing structures, the basic challenges of designing morphing structures are listed. The concept of Pressure Actuated Cellular Structures (PACS) is arranged within the recent morphing activities and it is shown that it complies with the underlying demands. Systematically divided into energy-related and structural subcomponents the working principle is illuminated and relationships between basic design parameters are expressed. The analytical background describing the physical mechanisms of PACS is presented in concentrated manner. This work focuses on the procedure of dimensioning, realizing and experimental testing of a single cell and a single row cantilever made of PACS. The experimental outcomes as well as the results from the FEM computations are used for evaluating the analytical methods. The functionality of the basic principle is thus validated and open issues are determined pointing the way ahead

NMR-Spectroscopic Investigations in Asymmetric Brønsted Acid Catalysis – Structural Space, Hydrogen Bonding and Non-Covalent Interactions

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

Tilting the Balance: London Dispersion Systematically Enhances Enantioselectivities in Brønsted Acid Catalyzed Transfer Hydrogenation of Imines

London dispersion (LD) is attracting more and more attention in catalysis since LD is ubiquitously present and cumulative. Since dispersion is hard to grasp, recent research has concentrated mainly on the effect of LD in individual catalytic complexes or on the impact of dispersion energy donors (DEDs) on balance systems. The systematic transfer of LD effects onto confined and more complex systems in catalysis is still in its infancy, and no general approach for using DED residues in catalysis has emerged so far. Thus, on the example of asymmetric Brønsted acid catalyzed transfer hydrogenation of imines, we translated the findings of previously isolated balance systems onto confined catalytic intermediates, resulting in a systematic enhancement of stereoselectivity when employing DED-substituted substrates. As the imine substrate is present as Z- and E-isomers, which can, respectively, be converted to R- and S-product enantiomers, implementing tert-butyl groups as DED residues led to an additional stabilization of the Z-imine by up to 4.5 kJ/mol. NMR studies revealed that this effect is transferred onto catalyst/imine and catalyst/imine/nucleophile intermediates and that the underlying reaction mechanism is not affected. A clear correlation between ee and LD stabilization was demonstrated for 3 substrates and 10 catalysts, allowing to convert moderate–good to good–excellent enantioselectivities. Our findings conceptualize a general approach on how to beneficially employ DED residues in catalysis: they clearly showcase that bulky alkyl residues such as tert-butyl groups must be considered regarding not only their repulsive steric bulk but also their attractive properties even in catalytic complexes

Bidentate substrate binding in Brønsted acid catalysis: structural space, hydrogen bonding and dimerization

BINOL derived chiral phosphoric acids (CPAs) are a prominent class of catalysts in the field of asymmetric organocatalysis, capable of transforming a wide selection of substrates with high stereoselectivities. Exploiting the Bronsted acidic and basic dual functionality of CPAs, substrates with both a hydrogen bond acceptor and donor functionality are frequently used as the resulting bidentate binding via two hydrogen bonds is expected to strongly confine the possible structural space and thus yield high stereoselectivities. Despite the huge success of CPAs and the popularity of a bidentate binding motif, experimental insights into their organization and origin of stereoinduction are scarce. Therefore, in this work the structural space and hydrogen bonding of CPAs and N-(ortho-hydroxyaryl) imines (19 CPA/imine combinations) was elucidated by low temperature NMR studies and corroborated by computations. The postulated bidentate binding of catalyst and substrate by two hydrogen bonds was experimentally validated by detection of trans-hydrogen bond scalar couplings. Counterintuitively, the resulting CPA/imine complexes showed a broad potential structural space and a strong preference towards the formation of [CPA/imine](2) dimers. Molecular dynamics simulations showed that in these dimers, the imines form each one hydrogen bond to two CPA molecules, effectively bridging them. By finetuning steric repulsion and noncovalent interactions, rigid and well-defined CPA/imine monomers could be obtained. NOESY studies corroborated by theoretical calculations revealed the structure of that complex, in which the imine is located in between the 3,3 '-substituents of the catalyst and one site of the substrate is shielded by the catalyst, pinpointing the origin or stereoselectivity for downstream transformations

Brønsted acid catalysis – the effect of 3,3′-substituents on the structural space and the stabilization of imine/phosphoric acid complexes

BINOL derived chiral phosphoric acids (CPAs) are widely known for their high selectivity. Numerous 3,3 0 substituents are used for a variety of stereoselective reactions and theoretical models of their effects are provided. However, experimental data about the structural space of CPA complexes in solution is extremely rare and so far restricted to NMR investigations of binary TRIP/imine complexes featuring two E-and two Z-imine conformations. Therefore, in this paper the structural space of 16 CPA/imine binary complexes is screened and 8 of them are investigated in detail by NMR. For the first time dimers of CPA/ imine complexes in solution were experimentally identified, which show an imine position similar to the transition state in transfer hydrogenations. Furthermore, our experimental and computational data revealed an astonishing invariance of the four core structures regardless of the different steric and electronic properties of the 3,3 0 -substituent. However, a significant variation of E/Z-ratios is observed, demonstrating a strong influence of the 3,3 0 - substituents on the stabilization of the imine in the complexes. These experimental E/Z-ratios cannot be reproduced by calculations commonly applied for mechanistic studies, despite extensive conformational scans and treatment of the electronic structure at a high level of theory with various implicit solvent corrections. Thus, these first detailed experimental data about the structural space and influence of the 3,3 0 -substituent on the energetics of CPA/imine complexes can serve as basis to validate and improve theoretical predictive models

Brønsted Acid Catalysis ‐ Controlling the Competition of Monomeric versus Dimeric Reaction Pathway Enhances Stereoselectivities

Chiral phosphoric acids (CPA) have become a privileged catalyst type in organocatalysis, but the selection of the optimum catalyst is still challenging. So far hidden competing reaction pathways may limit the maximum stereoselectivities and the potential of prediction models. In CPA catalyzed transfer hydrogenation of imines, we identified for many systems two reaction pathways with inverse stereoselectivity, featuring as active catalyst either one CPA or a hydrogen bond bridged dimer. NMR measurements and DFT calculations revealed the dimeric intermediate and a stronger substrate activation via cooperativity. Both pathways are separable: Low temperatures and high catalysts loadings favor the dimeric pathway (ee up to -98%), while low temperatures with reduced catalyst loading favor the monomeric pathway and give significantly enhanced ee (92-99% ee; prior 68-86% at higher temperatures). Thus, a broad impact is expected on CPA catalysis regarding reaction optimization and prediction

Enantioselective [2 + 2] Photocycloaddition via Iminium Ions: Catalysis by a Sensitizing Chiral Brønsted Acid

N,O-Acetals derived from α,β-unsaturated β-aryl substituted aldehydes and (1-aminocyclohexyl)methanol were found to undergo a catalytic enantioselective [2 + 2] photocycloaddition to a variety of olefins (19 examples, 54–96% yield, 84–98% ee). The reaction was performed by visible light irradiation (λ = 459 nm). A chiral phosphoric acid (10 mol %) with an (R)-1,1′-bi-2-naphthol (binol) backbone served as the catalyst. The acid displays two thioxanthone groups attached to position 3 and 3′ of the binol core via a meta-substituted phenyl linker. NMR studies confirmed the formation of an iminium ion which is attached to the acid counterion in a hydrogen-bond assisted ion pair. The catalytic activity of the acid rests on the presence of the thioxanthone moieties which enable a facile triplet energy transfer and an efficient enantioface differentiation