NMR as a Tool for Studying Rapid Equilibria: Tautomerism

Tautomerism is a chemical equilibrium which involves rapid transference of a hydrogen atom. Its importance in biochemistry, medicinal chemistry, pharmacology and organic synthesis, as well as the wide variety of molecules in which it occurs, makes it an interesting chemical issue to be studied. NMR bears the advantage of allowing equilibrium observation without shifting it. The aim of this work is to sum up a variety of experiments that can be carried out on tautomeric equilibria in order to obtain structural and mechanistic information. In every case, the two (or more) major tautomeric forms must have relatively low conversion rates, i.e., they must exist long enough to survive (in average) the NMR experiment and then show different but overlapped NMR spectra. Assignation of the peaks to their corresponding tautomeric form has to be done with regarding signal integration, multiplicity and chemical shift of the signals. Theoretical calculations might be carried out in order to do this assignation. Once found two (or more) independent and non-overlapped peaks corresponding to each tautomer, their integration permits tautomeric contents and tautomerization constants calculation. Herein, equilibrium shifts caused by the presence of substituents (causing electronic and steric effects), solvents (interacting in different ways with the tautomers), internal chemical interactions (such as hydrogen bonds), tautomer-tautomer interactions (producing the formation of dimers) and temperature variation are discussed using a variety of compounds, such as ketonitriles, ketoamides and salicylaldimines, among others. All these facts give information about the causes of the stabilization or destabilization of different tautomeric forms.

Keywords: NMR, Solvent effect, Substituent effect, Tautomerism, Theoretical calculations.