Application of residual dipolar couplings in organic compounds

Abstract

INTRODUCTIONThe classic NMR strategy for determining the structure or stereochemistry of small molecules is by using a combination of nuclear overhauser effect (NOE) and scalar J couplings. dependence, where r is the internuclear distance and can be used to connect protons up to 5Å apart. 2 1 H-1 H NOEs have the most utility in small-molecule studies. H-X NOEs usually require isotopic labeling, which can be difficult synthetically for small molecules.1 H-1 H scalar couplings are easy to measure and have high information content; 3 J HH leads to the relative orientations of the atoms by sequential connectivity and estimation of dihedral angles through the well-known Karplus equation.3 Long-range heteronuclear J couplings ( >2 J XH ) are also useful for structural determinations but the data are more difficult to obtain. Typically, these involve 13 C or 15 N as the X-nucleus and if the sample is not isotopically enriched the experiment, such as heteronuclear multiple bond coherence spectroscopy (HMBC), 4,5 can be very time consuming. If the molecule of interest has an overall dearth of protons, has NOEs that cannot be assigned unambiguously or has breaks in the NOE or scalar connectivities, the typical NOE/J analysis fails. Additionally, in order to obtain the relative orientation of remote centers, multiple NOE or J-coupling connections have to be performed in series to transverse the entire molecule. The further away the stereocenters are from each other, the greater the number of necessary connections and measurements needed to confirm unambiguously the connectivity. If one of the connections fails, the pathway fails. Thus, a method that does not rely upon these connectivities would be extremely useful for stereochemistry

Dielectric permittivity and temperature effects on spin–spin couplings studied on acetonitrile

“…[39] There is also a relatively new trend to use weakly aligning conditions for small molecule structure determination or the solution of stereochemical problems. [40,41] To this end, new aligning media are being developed for water-insoluble substances. In these media, the main solvent is hydrophobic which usually results in a low-dielectric permittivity (for instance, chloroform-or benzene-compatible gels, [42,43] reversed lyotropics, etc).…”

Determining the Stereochemistry of Molecules from Residual Dipolar Couplings (RDCs)

“…There are of course many more, most of which can be found in the cited reviews. 7 -9,12,30, 31 In a simple but frequently met case, RDCs can be applied to rigid compounds of known (relative) configuration to assign resonances of prochiral groups. For this treatment, a single reasonable structure (e.g., a crystal structure) may be satisfying to fully address this question.…”

Assessment of solvent effects: do weak alignment media affect the structure of the solute?

“…4,5 Utilizing RDCs led to increased accuracy and precision of three-dimensional (3D) solution structures of biological macromolecules (nucleic acids, proteins, carbohydrates, and their complexes) 6 -9 and opened the opportunity of complete de novo 3D structure determination. 10 Recently, alignment media and RDC-based strategies have also become popular for the investigation of structural and conformational properties of organic molecules, 11 as well as for complete structure determination. 12,13 In assessing the successes of using partial alignment in biomolecular structure determination, it seems prudent to readdress issues concerning accuracy, reliability and applicability of alignment methodologies, which limited the application of NMR to structure determination of strongly oriented small molecules.…”