Solid-state nuclear magnetic resonance

Solid-state NMR (ssNMR) spectroscopy is a technique for characterizing atomic level structure in solid materials e.g. powders, single crystals and amorphous samples and tissues using nuclear magnetic resonance (NMR) spectroscopy. The anisotropic part of many spin interactions are present in solid-state NMR, unlike in solution-state NMR where rapid tumbling motion averages out many of the spin interactions. As a result, solid-state NMR spectra are characterised by larger linewidths than in solution state NMR, which can be utilized to give quantitative information on the molecular structure, conformation and dynamics of the material. Solid-state NMR is often combined with magic angle spinning to remove anisotropic interactions and improve the resolution as well as the sensitivity of the technique. Nuclear spin interactions The resonance frequency of a nuclear spin depends on the strength of the magnetic field at the nucleus, which can be modified by isotropic (e.g. chemical s

Ligand synthesis for homogeneous catalysis

Michael Maurin

Organophosphorus compounds found applications in varied fields of the organic chemistry: they are particularly present in natural compounds such as the deoxyribonucleic acid (DNA) and in the field of catalysis in which their utility is also proven. Thus, this thesis work first focused on the preparation of various phosphorus ligands utilizable in transition metal catalysed reactions. Being given the importance of this type of reaction in organic synthesis, it appears essential to have many ligands at disposal in order to fine-tune and to optimize the reaction conditions as much as possible. Thus, the first objective of this work was to propose a simple and general method for the preparation of monodentate phosphorus ligands. Based on the use of phosphites in substitution for the usual phosphorus trihalides, this method was initially tested during the preparation of different simple triarylphosphines. Thereafter, this method was extended to the synthesis of new ligands having more complex structures. The yields obtained for the latter as well as the variety of the substrates authorized by this method confirmed its value and suggested its application to the synthesis of new heteroaromatic phosphines. The preparation of bidentate phosphorus ligands based on chiral biphenyl motifs was then addressed. For that purpose, the 2,2',6,6' -tetrabromobiphenyl was chosen as a pivot substrate for the development of a modular synthetic approach. Indeed, by means of successive halogen/metal permutational exchanges and after treatment with the suitable electrophile, it was possible to functionalize this substrate, isolate each atropisomer in enantiomerically pure form, and finally convert each one of those into chiral biphenylbisphosphines. In addition, it was also possible, during the synthesis of these ligands, to evaluate the rotational stability of some enantiomerically pure dilithiobiphenyls by means of dynamic nuclear magnetic resonance experiments.

EPFL2007

Indirect detection of nitrogen-14 in solid-state NMR spectroscopy

Simone Cavadini

This thesis describes new methods for the detection of 14N nuclei by solid-state nuclear magnetic resonance. So far, the low natural abundance (0.4 %) 15N isotope has been widely used to study nitrogen-containing samples because of its spin-1/2 nature. The limited use of the spin-1 isotope 14N (natural abundance 99.6 %) in NMR is due to its strong quadrupolar coupling constant, which leads to very broad spectra that are difficult to excite uniformly and equally difficult to detect, requiring broad receiver bandwidths. The new methods presented in this work result from two main projects covering the indirect detection of 14N via carbon and via protons. The indirect detection of 14N can be achieved by heteronuclear multiple- or single-quantum correlation (HMQC or HSQC) experiments, which rely on the transfer of coherence from a neighboring spin S = 1/2 (13C or 1H) to single- (SQ) or double-quantum (DQ) transitions of 14N nuclei. These methods allow one to observe 14N powder patterns with enhanced sensitivity. These spectra depend on the quadrupolar coupling constant CQ (typically a few MHz), the asymmetry parameter ηQ, and on the orientation of the internuclear vector rIS between the I (14N) and S (13C or 1H) nuclei with respect to the quadrupolar tensor. These parameters reveal valuable information about the structure and dynamics of nitrogen-containing solids. The indirect detection methods are discussed in detail, covering the optimization of experimental parameters; subsequently, applications to the study of amino acids at different magnetic fields are demonstrated.

EPFL2009

Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy

Matthias Huber, Sina Maren Reckel, Henning Paul-Julius Stahlberg

Inflammasomes are multiprotein complexes that control the innate immune response by activating caspase-1, thus promoting the secretion of cytokines in response to invading pathogens and endogenous triggers. Assembly of inflammasomes is induced by activation of a receptor protein. Many inflammasome receptors require the adapter protein ASC [apoptosis-associated speck-like protein containing a caspase-recruitment domain (CARD)], which consists of two domains, the N-terminal pyrin domain (PYD) and the C-terminal CARD. Upon activation, ASC forms large oligomeric filaments, which facilitate procaspase-1 recruitment. Here, we characterize the structure and filament formation of mouse ASC in vitro at atomic resolution. Information from cryo-electron microscopy and solid-state NMR spectroscopy is combined in a single structure calculation to obtain the atomic-resolution structure of the ASC filament. Perturbations of NMR resonances upon filament formation monitor the specific binding interfaces of ASC-PYD association. Importantly, NMR experiments show the rigidity of the PYD forming the core of the filament as well as the high mobility of the CARD relative to this core. The findings are validated by structure-based mutagenesis experiments in cultured macrophages. The 3D structure of the mouse ASC-PYD filament is highly similar to the recently determined human ASC-PYD filament, suggesting evolutionary conservation of ASC-dependent inflammasome mechanisms.

Proceedings of the National Academy of Sciences2015

Ligand synthesis for homogeneous catalysis

Michael Maurin

EPFL2007