Probing Long‐Range Anisotropic Interactions: a General and Sign‐Sensitive Strategy to Measure ¹H–¹H Residual Dipolar Couplings as a Key Advance for Organic Structure Determination

Abstract

Residual dipolar couplings (RDCs) are amongst the most powerful NMR parameters for organic structure elucidation. In order to maximize their effectiveness in increasingly complex cases such as flexible compounds, a maximum of RDCs between nuclei sampling a large distribution of orientations is needed, including sign information. For this, the easily accessible one‐bond 1H–13C RDCs alone often fall short. Long‐range 1H–1H RDCs are both abundant and typically sample highly complementary orientations, but accessing them in a sign‐sensitive way has been severely obstructed due to the overflow of 1H–1H couplings. Here, we present a generally applicable strategy that allows the measurement of a large number of 1H–1H RDCs, including their signs, which is based on a combination of an improved PSYCHEDELIC method and a new selective constant‐time β‐COSY experiment. The potential of 1H–1H RDCs to better determine molecular alignment and to discriminate between enantiomers and diastereomers is demonstrated.

TITANIA: Model-Free Interpretation of Residual Dipolar Couplings in the Context of Organic Compounds

“…RDC data with better linear independence (see 1-D and 1-E ) converge to the correct solution when using long-range couplings. Even a few long-range couplings, which are indeed available from modern experiments, will improve accuracy in the vector orientations. The few examples, which converged to the wrong configuration, showed strong distortions of the tetrahedral geometries, indicating the correct structure by showing the inverse RDC vector solution at the respective stereogenic center, thus allowing an easy identification by the operator.…”

“…The basis for all sets consists of all 1 D CH (and derived methyl 1 D CC ) couplings ( 1-A11 ). Additional six 3 D HH couplings wrapping the structure once ( 1-A17 ), all 2 D HH and 3 D HH couplings ( 1-A23 ), an experimental set defined by 31 RDCs reported in the literature ( 1-A31 ) and all possible n D HH couplings ( 1-A39 ) were chosen as meaningful set sizes. The RDC nuclei of the individual runs are listed in the Supporting Information (see Table S-21).…”

“…The wealth of RDC data experimentally accessible in labeled biomacromolecules enabled the development and broad application of these methods in that field. Modern developments in alignment media − compatible with small organic molecules, introducing different alignment conditions combined with new NMR pulse sequences − designed to give easier access to crucial long-range n D XH and n D HH RDCs may now finally allow extending the model-free approach also to organic compounds. This is investigated within the current manuscript.…”

Trendbericht: Kernmagnetische Resonanz

“…16 Multipletts sehr genau und mit Vorzeichen in reinen 1 H-Experimenten messbar. 17) Weiterhin ist jetzt durch das homonuklear entkoppelte EASY-ROESY 18) ein Experiment verfügbar, das wohl langfristig die konventionellen ROESY-Experimente wegen der hohen erreichbaren Spektrenqualität ablösen wird (Abbildung 7). Mit der neuen GEM-STONE-Selektion 19) lassen sich ein-zelne Signale mit überlagernden Multipletts in quasi allen Standardkorrelationsexperimenten anregen.…”

“…Polymermizellen für pharmazeutischen Wirkstofftransport, hier Curcumin, wurden auf Basis von NMR beladungsabhängig modelliert, obwohl sie keine definierte Struktur haben (Abbildung 10). 45) Quadrupolkerne wie 17 47) Die sehr schnelle Probenrotation wird im Zusammenhang mit Proteinen bevorzugt bei sehr hohem B 0 -Feld (zirka > 20 Tesla) genutzt. In paramagnetischen Systemen kann die Kombination mit relativ niedrigem B 0 (zirka < 5 Tesla) jedoch hilfreich für 7 Li-NMR sein, zum Beispiel bei Batteriematerialien.…”