Constitutional, Configurational, and Conformational Analysis of Small Organic Molecules on the Basis of NMR Residual Dipolar Couplings

Abstract

Dedicated to Professor Aksel BothnerBy on the occasion of his 90th birthday configuration determination · conformation analysis · NMR spectroscopy · residual dipolar couplings · structure elucidation NMR spectroscopy is arguably one of the most powerful tools available to chemists for the structural analysis of molecules. NMR experiments based on the nuclear Overhauser enhancement (NOE) [1] and on the analysis of 3 J coupling constants [2] have been used intensively in the configurational and conformational analysis of small organic molecules. However, as these two NMR parameters provide only localized structural information, they fail to provide information on the relative configuration of remotely located molecular fragments.Unlike NOEs and 3 J coupling constants, the direct spinspin interaction known as dipolar coupling (D ij ; Figure 1) can provide very powerful structural information of a nonlocal character.[3] The value of D ij between two nuclei i and j (which can either be bonded to one another or not directly connected) depends not only on the distance between them (r), but also on the angle of the internuclear vector (r ij ) with respect to the direction of the magnetic field (B 0 ), which acts as a global axis of reference. Hence, from the equation in Figure 1, it can be inferred that a unique combination of dipolar-coupled pairs of spins can produce a unique set of dipolar couplings, which in turn can enable unambiguous determination of the relative spatial arrangement of atoms in a molecule. This spatial arrangement reflects the constitution, configuration, and preferred conformation of the molecule.When the concept is explained in this way, the use of dipolar couplings for the analysis of small molecules sounds very simple and straightforward. However, the size of dipolar couplings is on the order of kilohertz. In solid-state powders, all possible spatial orientations adopted by molecules lead to extremely broad lines in the NMR spectrum, which makes the extraction of individual dipolar couplings impossible. In solution, dipolar couplings average out as a result of isotropic molecular tumbling and are not observable in the NMR spectrum (isotropic conditions). However, if molecules are forced to adopt a minor degree of alignment in solution, a measurable fraction of the original dipolar coupling, known as residual dipolar coupling (RDC), is observed in the NMR spectrum. RDCs conserve the same structural information provided by the original dipolar couplings, since they are scaled down proportionally. From a practical standpoint, RDCs can be measured relatively easily provided that the degree of alignment is weak (0.01-0

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