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.