Christina M. Thiele

Photoswitchable Catalysts: Correlating Structure and Conformational Dynamics with Reactivity by a Combined Experimental and Computational Approach

Photocontrol of a piperidines Brønsted basicity was achieved by incorporation of a bulky azobenzene group and could be translated into pronounced reactivity differences between ON- and OFF-states in general base catalysis. This enabled successful photomodulation of the catalysts activity in the nitroaldol reaction (Henry reaction). A modular synthetic route to the photoswitchable catalysts was developed and allowed for preparation and characterization of three azobenzene-derived bases as well as one stilbene-derived base. Solid-state structures obtained by X-ray crystal structure analysis confirmed efficient blocking of the active site in the E isomer representing the OFF-states, whereas a freely accessible active site was revealed for a representative Z isomer in the crystal. To correlate structure with reactivity of the catalysts, conformational dynamics were thoroughly studied in solution by NMR spectroscopy, taking advantage of residual dipolar couplings (RDCs), in combination with comprehensive DFT computational investigations of conformations and proton affinities.

Speeding up the measurement of one-bond scalar (1J) and residual dipolar couplings (1D) by using non-uniform sampling (NUS)

The accurate and precise measurement of one-bond scalar and residual dipolar coupling (RDC) constants is of prime importance to be able to use RDCs for structure determination. If coupling constants are to be extracted from the indirect dimension of HSQC spectra a significant saving of measurement time can be achieved by non-uniform sampling (NUS). Coupling constants can either be obtained with the same precision as in traditionally acquired spectra in a fraction of the measurement time or the precision can be significantly improved if the same amount of measurement time as for traditionally acquired spectra is invested. The application of NUS for the measurement of (1)J (scalar coupling constants) and (1)T (total couplings constants) from different kinds of ω(1)-coupled spectra (including also J-scaled ones) is examined in detail and the possible gains in time or resolution are discussed. When using the newly proposed compressed sensing (CS) algorithm for processing, the quality of the spectra is comparable to the traditionally sampled ones.

Designing Structural Motifs for Clickamers: Exploiting the 1,2,3‐Triazole Moiety to Generate Conformationally Restricted Molecular Architectures

Noncovalent interactions, especially hydrogen-bonding interactions as well as electrostatic forces, confined within one macromolecule are the key to designing foldamers that adopt well-defined conformations in solution. In the context of significant recent activities in the area of triazole-connected foldamers, so-called clickamers, we present a fundamental study that compares various model compounds that bear adjacent N-, O-, or F-heteroatom substituents. The interplay of attractive and repulsive interactions leads to rotational constraints around the single bonds attached to both the 1- and 4-positions of the 1,2,3-triazole moiety and should therefore be able to induce well-defined conformational preferences in higher oligomers and polymers, that is, foldamers. Various compounds were synthesized and characterized with regard to their preferred conformations in all three aggregation states--that is, in the gas phase, in solution as well as in the solid state--by employing DFT calculations, NMR spectroscopic experiments, and X-ray crystallography, respectively. On the basis of the thus-obtained general understanding of the conformational behavior of the individual connection motifs, heterostructures were prepared from different motifs without affecting their distinct folding characteristics. Therefore, this work provides a kind of foldamer construction kit, which should enable the design of various clickamers with specific shape and incorporated functionality.

On the Treatment of Conformational Flexibility when Using Residual Dipolar Couplings for Structure Determination

Mission possible! The motional averaging of NMR spectroscopic data complicates the determination of conformation and relative configuration in flexible organic molecules. Two alternative routes are discussed for the treatment of conformational equilibrium in a moderately flexible compound (see the superposition of the two conformers of the butyrolactone studied) when residual dipolar couplings are used.

Orientational Properties of Poly‐γ‐benzyl‐L‐glutamate: Influence of Molecular Weight and Solvent on Order Parameters of the Solute

Residual dipolar couplings (RDCs) have recently become increasingly important in organic structure determination due to their unique information content. One main limitation for the use of RDCs in organic compounds, however, is that the compound in question needs to be oriented with respect to the magnetic field in order to measure RDCs. So far, there are very few possibilities for modulating the induced degree of orientation. The situation is even worse when chiral orienting media are considered, which could allow absolute configuration determination in the future. We have conducted a systematic investigation into modulating the orientation induced by one chiral orienting medium, namely organic solutions of PBLG (poly-gamma-benzyl-L-glutamate), as a function of its molecular weight and the organic co-solvent used, and have obtained significant insights into factors that influence the order induced. With increasing molecular weight of the polypeptide the orientation of the solutes decreases, leading to well-resolved spectra with improved line shapes. This can be attributed exclusively to the fact that the critical concentration of the liquid-crystalline phase decreases with increasing molecular weight (pure dilution effect). Any influence of increasing flexibility on the orientation can be ruled out.

Accurate determination of one-bond heteronuclear coupling constants with "pure shift" broadband proton-decoupled CLIP/CLAP-HSQC experiments.

We report broadband proton-decoupled CLIP/CLAP-HSQC experiments for the accurate determination of one-bond heteronuclear couplings and, by extension, for the reliable measurement of small residual dipolar coupling constants. The combination of an isotope-selective BIRD((d)) filter module with a non-selective (1)H inversion pulse is employed to refocus proton-proton coupling evolution prior to the acquisition of brief chunks of free induction decay that are subsequently assembled to reconstruct the fully-decoupled signal evolution. As a result, the cross-peaks obtained are split only by the heteronuclear one-bond coupling along the F2 dimension, allowing coupling constants to be extracted by measuring simple frequency differences between singlet maxima. The proton decoupling scheme presented has also been utilized in standard HSQC experiments, resulting in a fully-decoupled pure shift correlation map with significantly improved resolution.

EASY ROESY : reliable cross-peak integration in adiabatic symmetrized ROESY

Estimates of intramolecular distances are essential for structure determination. For medium-sized molecules, ROESY NMR is the method of choice for obtaining distances. However, the integration of R ...

Polyacetylenes as Enantiodifferentiating Alignment Media

The availability of residual dipolar couplings (RDCs) measured in weakly aligned media has had a major impact on the structural characterization of dissolved (chiral) molecules by NMR spectroscopy. This has been and still is especially true for biomacromolecules but more recently, the field has seen a rapidly increasing interest in the application of RDCs to solve structural problems for small molecules, too. 3] This, at first sight surprising fact, is by no means a back-extension, because the molecules under investigation pose problems being absent in the above-mentioned biopolymers. In contradiction to the latter many small molecules contain stereogenic units of unknown relative and absolute configuration. Given the fact that configurational analysis is always a problem of conformational analysis at the same time, the simultaneous treatment of both structural aspects is a necessity to solve the stereochemical problem exhaustively. With the advent of RDCs as a new NMR parameter containing distance and angle information the scope of NMRbased stereochemical analysis has been broadened considerably. This is mainly because of the fact that RDCs deliver conformationally relevant information without the need for parametrization as is the case for the evaluation of scalar couplings. Moreover, RDCs are global parameters not relying on short-range interactions like cross-relaxation (nuclear Overhauser effect, NOE) or cross-correlated relaxation. A precondition for the measurement of RDCs, as anisotropic NMR parameters, is to partially orient the analyte with respect to the magnetic field (weak alignment: RDC amounts approximately 10 3 of the maximum dipolar coupling). This can be done either by stretched polymer gels (SAG = strain-induced alignment in a gel) or by dissolving the compound in a lyotropic liquid-crystalline (LLC) phase. In the last years considerable progress has been made in the field of these orienting or alignment media especially for typical organic molecules being insoluble in water. On the other hand if the determination of the absolute configuration of a chiral, nonracemic water-insoluble compound is the goal of the investigation, it is necessary to orient the analyte in an enantiodifferentiating manner. This in turn is possible only if the alignment medium is itself chiral and of uniform configuration. The number of media fulfilling these criteria is still extraordinary small. As far as chiral LLC phases are concerned, only the homopolypeptide-based LLC phases derived from poly-g-benzyl-l/d-glutamate (PBLG/PBDG), poly-g-ethyl-l-glutamate (PELG/PEDG), and poly-e-carboxybenzoyl-l/d-lysin (PCBLL/PCBDL) as well as a recently introduced polyguanidine are known to meet the described needs. Moreover, Luy and co-workers have shown that gelatin cross-linked by accelerated electrons (e -gelatin) allows for the distinction of enantiomers in DMSO and DMSO/D2O mixtures at temperatures up to 60 8C. Despite our encouraging results with the polyguanidines, we decided to look for alternative helically chiral polymers capable of forming LLC phases. This decision was driven by a number of drawbacks associated with the polyguanidines. First of all the linewidths of the NMR signals from the analyte are rather large which hampers a precise determination of RDCs. Furthermore, the induced alignment is too strong which may lead to strong coupling artifacts. Finally, the purification of the noncrystalline carbodiimide monomers suffers from decomposition during chromatography. Within the family of helically chiral polymers 12] the amino-acid-stabilized polyisocyanides and polyacetylenes look most promising. Both polymer types are known to form LLC phases 14f,g,h] in a number of organic solvents and they are characterized by large persistence lengths 14h] (depending on the solvent) which should reduce the critical concentration for the phase transition. Moreover, the synthesis of the corresponding monomers is straightforward and their transition-metal-induced polymerization works efficiently with a high tolerance for functional groups. 16] In this contribution we would like to describe the suitability of the valine-derived polyacetylene p1 and its enantiomer p2 as alignment media. The synthesis of monomer 1 was achieved in three steps starting from 4-iodobenzoic acid ethyl ester 2 and valine 3 (Scheme 1; for a detailed description see the Supporting Information). According to the work of Okoshi and Yashima 18] the polymerization of 1 was initiated by [Rh(nbd)Cl]2 delivering polymer p1 as a yellow solid (nbd = norbornadiene). This polymerization reaction was repeated three times whereby a total of four different polymer samples (p1 a, p1 b, p1c, and [*] Dipl.-Chem. N.-C. Meyer, Dipl.-Ing. A. Krupp, Dipl.-Ing. V. Schmidts, Prof. Dr. C. M. Thiele, Prof. Dr. M. Reggelin Technische Universit t Darmstadt Clemens Schçpf Institut f r Organische Chemie und Biochemie Petersenstrasse 22, 64287 Darmstadt (Germany) E-mail: re@punk.oc.chemie.tu.darmstadt.de Homepage: deepthought.oc.chemie.tu-darmstadt.de

Is Enantiomer Assignment Possible by NMR Spectroscopy Using Residual Dipolar Couplings from Chiral Nonracemic Alignment Media?—A Critical Assessment

The discovery of Jean-Baptiste Biot in 1815 that optical activity is not a property bound to a certain aggregation state of matter but a property of the constituting molecules themselves, has had an enormous influence on the structural models that chemists developed at the end of the 19th century, long before the description of the chemical bond was based on quantum mechanics. Pasteur achieved the first separation of enantiomers in 1847, namely by crystallization of a racemic tartrate mixture that separated the two enantiomers into enantiomorphic crystals, solutions of which rotated the plane of linearly polarized light in opposite directions. Not until 1951, when Bijvoet used anomalous X-ray diffraction, it was possible to assign the absolute configuration to a specific enantiomer. However, anomalous X-ray diffraction has not put the problem of assigning absolute configurations to rest, because many chemical compounds cannot be crystallized. Moreover, anomalous X-ray diffraction of molecules that consist exclusively of lightweight atoms commonly lacks the needed accuracy to allow unambiguous assignment of absolute configurations. An alternative method for resolving enantiomers is to convert them to diastereoisomers, either by chemical derivatization with chiral nonracemic moieties or by intermolecular coordination with chiral nonracemic reagents. In this way it is possible to determine absolute configuration from NMR observables, most commonly chemical shifts. The use of chiroptical spectroscopies such as optical rotatory dispersion, and electronic or vibrational circular dichroism is well established, sometimes in combination with ab initio calculations. Further methods are conceivable but impractical momentarily. Yet, there is currently not a simple and universally applicable approach to determine the absolute configuration of molecules with few stereogenic centers. Two recent papers published in 2007 and 2011 have therefore created a lot of excitement in the chemistry and NMR spectroscopy communities. Their titles are: “Stereochemical Identification of (R)and (S)-Ibuprofen Using Residual Dipolar Couplings, NMR, and Modeling”, henceforth called “article 1”, and more recently: “Spin-Selective Correlation Experiment for Measurement of Long-Range J Couplings and for Assignment of (R/S) Enantiomers from the Residual Dipolar Couplings and DFT”, henceforth called “article 2”. Both articles describe the assignment of the absolute configuration of the chiral molecules, ibuprofen 1 (article 1) and 4-methyl-1,3-dioxolan-2-one 2 (article 2), using NMR spectroscopy in chiral nonracemic alignment media (Figure 1). Under chiral nonracemic conditions, the authors measured residual dipolar couplings (RDCs), a NMR parameter only visible in oriented samples, such as in liquid crystals, but not in isotropic solvents. The interaction of the enantiomers with the chiral nonracemic alignment medium gives rise to diastereomorphic associates for which reason the authors indeed found different sets of anisotropic parameters for each enantiomer, in total

Variable angle NMR spectroscopy and its application to the measurement of residual chemical shift anisotropy

The successful measurement of anisotropic NMR parameters like residual dipolar couplings (RDCs), residual quadrupolar couplings (RQCs), or residual chemical shift anisotropy (RCSA) involves the partial alignment of solute molecules in an alignment medium. To avoid any influence of the change of environment from the isotropic to the anisotropic sample, the measurement of both datasets with a single sample is highly desirable. Here, we introduce the scaling of alignment for mechanically stretched polymer gels by varying the angle of the director of alignment relative to the static magnetic field, which we call variable angle NMR spectroscopy (VA-NMR). The technique is closely related to variable angle sample spinning NMR spectroscopy (VASS-NMR) of liquid crystalline samples, but due to the mechanical fixation of the director of alignment no sample spinning is necessary. Also, in contrast to VASS-NMR, VA-NMR works for the full range of sample inclinations between 0° and 90°. Isotropic spectra are obtained at the magic angle. As a demonstration of the approach we measure ¹³C-RCSA values for strychnine in a stretched PDMS/CDCl₃ gel and show their usefulness for assignment purposes. In this context special care has been taken with respect to the exact calibration of chemical shift data, for which three approaches have been derived and tested.