Rotamers- assigned by a simple NMR experiment


Rotamers are conformational isomers where interconversion by rotation around a single bond is restricted and an energy barrier has to be overcome in order to convert one conformer to another.  When this rotation strain barrier is high enough to allow for the isolation of the conformers then the isomers become atropoisomers. Rotamers are however not separable and their existence normally complicates the 1H NMR interpretation. Variable temperature (VT) NMR is the generally preferred method for  studying the equilibration of the rotamers and at low temperatures the spectrum is assigned to the frozen equilibrium and multiple peaks are observed while at higher temperatures the spectrum simplifies as the equivalent peaks are averaged out. Other methods for NMR simplification include the introduction of a complexing agent and solvent switching. All these techniques are inconvenient to the organic synthetic chemist when working on small scale. To overcome this problem, Steve Ley and co-workers have identified that chemical-exchange NMR experiments, such as 1D NOE, can be used to identified resonances corresponding to those protons in chemical exchange processes, therefore distinguishes rotamers form other impurities or even stereoisomers, in a non intrusive way.

 

In a 1D gradient NOE experiment, a selected peak is irradiated leading to a negative peak at the site of irradiation while those protons connected to the targeted frequency region through space appear as positive peaks (or in the opposite phase to the irradiated peak). On the other hands those protons undergoing chemical exchange with the irradiated protons will appear as negative peaks, (or in the same phase as the irradiated peak). Figure 1 illustrates this, where a chemical-exchange experiment can be used to distinguish sets of rotamers in the presence of diastereoisomers.

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Figure 1. (a) 1H NMR spectrum of a sample containing 3 and 4. Four NMR resonances (I, II, III, and IV) are observed corresponding to protons HA and HB in 3, 4, and their respective rotamers. (b) 1D gradient NOE spectrum after selective excitation of the resonance at 4.59 ppm (I) produces a single downfield resonance in the same phase at 4.28 ppm (III), indicating that resonances I and III belong to two rotamers of the same diastereomer (3) and that resonances due to one diastereomer do not transfer spin information via chemical exchange to the other. (c) 1D gradient NOE spectrum after selective excitation of the diastereomeric peak at 4.52 ppm (II) also produces a single downfield peak in the same phase (IV), indicating that resonances II and IV belong to two rotamers of the same diastereomer (4). Only the 5.2−4.1 ppm region is shown for clarity

Recently this technique has been applied by Proksch et al. to unambiguously determine the presence of four rotamers in two new depsipeptides. In this publication, they have also used 2D ROESY or NOESY experiments to find the same results.

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