NMR controlled titration elucidates protolytic and complex formation equilibria. Stability constants, dissociation constants and ion specific NMR parameter are obtained. Parameters and spectral features are used to derive the molecular structure of species involved in dynamic processes.
NMR-controlled Titrations – Principles and Progress: Monitoring protonation and complex formation equilibria in aqueous solutions
Gerhard Hägele*, Michael Grzonka, Jürgen Peters, Harald Spiegl, Hans Werner Kropp, Johannes Ollig, Stephan Hermens, Sven Augner, Carsten Uhlemann, Christian Pfaff, Zoltan Szakacs, Toni Keller, Martin Rindlispacher, Manfred Spraul.
Multifaceted interests in structural and analytical chemistry combine with such of medicine, pharmacy, biology, food sciences, agricultural chemistry and related fields, to understand structures and reactions for a broad range of model systems. Many important reactions in bio-relevant fields involve protolytic equilibria and complex formation processes. NMR spectroscopic methods assisted by classical analytical tools in combination with experimental and theoretical methods are used to study acids, bases and metal complexes. Within this context NMR-controlled titration proved to be a powerful method for research and production control. While initially performed by laborious series of single sample NMR experiments, more efficient, PC-guided, automated procedures were developed and applied successfully to a wide range of structural problems, as will be demonstrated with some examples in this paper.
Our main aim is to introduce readers to the technical aspects of a modern hyphenated technique combining aspects of potentiometric titration and NMR spectroscopy. This technique yields two- and three-dimensional graphical representations where NMR parameters are correlated with analytical parameters. This method is called “NMR-controlled titration“, “titration-dependent NMRspectroscopy“, or just “NMR-Titration” where the choice of terms depends largely on interests of individual users.
NMR-controlled titrations lead to characteristic dissociation and stability constants (pKa, pKb, logβ) and NMR parameters such as resonance frequencies, chemical shifts, coupling constants (ν, δ, J) for the individual species involved in macroscopic NMR controlled Titration 3 or microscopic equilibria. While ν, δ and J are subject to averaging processes governed by molar fractions, the spectral half width does not follow this simple principle.
Most likely HW, and henceforth the relaxation time T2*, is influenced by dynamic effects, hydrogen bonding, complex formation, where such phenomena are well observed and documented but not sufficiently well understood up to now. Future research should be directed towards these interesting aspects. NMR-controlled titration is an efficient tool to characterize carboxylic acids, amino acids, peptides and related structures involving phosphorylated and/or fluorinated analogues.