Lecture: «Structural Analysis of Natural and Synthetic Small Organic Molecules Using NMR in Anisotropic Media»
Prof. Roberto R. Gil (Carnegie Mellon University, Pittsburgh - USA)
CiQUS Seminar Room - 12:15 h
The 2D structure of most small molecules can be in principle straightforwardly determined by manual or automatic analysis of a set of experimental data that includes the molecular formula, a series of 1D and 2D NMR experiments providing trough-bond connectivity (COSY, TOCSY, HSQC, HMBC and ADEQUATE/INADEQUATE based experiments), and chemical shift predictions.
This is the main concept embedded in automatic structure elucidation programs. Once the 2D structure is available, the determination of the relative spatial arrangement (configuration and preferred conformation) of all atoms in the molecule is a more challenging task that it is commonly addressed in NMR by using NOE and 3J coupling constants analysis, as well as recent developments on the application of DFT calculation of 13C chemical shifts. However, it is difficult to assess how many samples are sitting on the laboratory’s refrigerators waiting for an independent methodology that could lift some of the ambiguities generated by the use of conventional NMR methods.
The development of the application of Residual Dipolar Couplings (RDCs) to the configurational and conformational analysis of small molecules has matured enough in the recent years to perform this task is an almost straightforward way, without even the need of using NOE and 3J coupling analysis, as it will be presented here for the analysis of rigid and semi-rigid small molecules.
Except for cases of very high flexibility, the methodology has proven to be extremely powerful, particularly in situations where the use of conventional NMR experiments, such as J coupling constants analysis and NOE-derived distances cannot provide a unique solution to the structural problem. Recent results on the application of Residual Chemical Shift Anisotropy (RCSAs) to the discrimination of molecular configuration will also be presented. Most of the results presented here use poly(methylmethacrylate) (PMMA) and poly(2-hydroxyethylmethacrylate) (poly-HEMA) based flexible gels, whose degree of alignment can be easily tuned by variable and reversible compression.