Determination of the relative pKa's of mixtures of organic acids using NMR titration experiments based on aliased 1H–13C HSQC spectra

Abstract

NMR titrations can be used to simultaneously determine the pKa's of mixtures of organic acids and bases provided chemical shifts are sensitive to their change of protonation states. Carbons are in principle better probes than protons because their chemical shifts are typically more sensitive to the changes in the electronic densities of the functional groups they are bound to. They are also less prone to overlap, do not suffer from second-order effects and are less sensitive to changes in solvent conditions. Recording HSQC spectra satisfactorily reduces the lack of sensitivity of carbon-detected experiments and the signal dispersion in two dimensions allows to automatically and finely track the drifts of a large number of signals simultaneously. The application of spectral aliasing to the carbon dimensions allows to quickly reach the high resolution required to precisely measure variations in carbon chemical shifts. The paper extends the methodology to the treatment of the data stemming from the simultaneous analysis of mixtures of compounds. It also introduces methods to improve the normalization process and deal with missing points. The application is not limited to the determination of pKa and can be readily extended to the determination of other chemical constants in experiments where the components of the mixture dynamically compete for substrates other than protons

Convenient and accurate insight into solution-phase equilibria from FlowNMR titrations

“…The analysis of high-value materials or use of reagents of low solubility may pose challenges where millimolar concentrations cannot be achieved in the ∼10 mL of solution required for the FlowNMR apparatus used here. We believe that the combination of modern NMR techniques such as fast and ultra-fast (UF) 2D NMR 96,97 or spectral aliasing 7 with low internal volume systems 98 can be used to overcome many of these barriers. Similarly, modern pure shift techniques 99 can be used to address challenges of spectral crowding resulting from peak overlap when dealing with large molecules or complex mixtures.…”

“…Hetero-nuclear NMR measurements using 13 C, 15 N, 19 F and 31 P and multi-dimensional correlation techniques allow for deeper insights into chemical interactions in solution. 4–7 Dynamic exchange within equilibrated mixtures may be probed and quantified by variable-temperature measurements and magnetisation transfer (EXSY) 8 or saturation transfer (CEST) 9 experiments, while aggregation states are amenable to study by diffusion ordered spectroscopy (DOSY). 10–12…”

“…Hetero-nuclear NMR measurements using 13 C, 15 N, 19 F and 31 P and multi-dimensional correlation techniques allow for deeper insights into chemical interactions in solution. [4][5][6][7] Dynamic exchange within equilibrated mixtures may be probed and quantified by variable-temperature measurements and magnetisation transfer (EXSY) 8 or saturation transfer (CEST) 9 experiments, while aggregation states are amenable to study by diffusion ordered spectroscopy (DOSY). [10][11][12] However, a practical limitation of NMR titrations is the necessity of carrying out these experiments ex situ on a large number of individual samples of precisely controlled concentration, or by repeatedly altering a single sample to build a titration curve with a suitable number of data points.…”

Controlling product selectivity during dioxygen reduction with Mn complexes using pendent proton donor relays and added base

“…1 H NMR spectroscopy was used to estimate a pK a of 18.7 for DIPEAHPF 6 in MeCN via titration and competition experiments (see ESI †). 31 Electrochemical analysis of 1 and 2…”

Determination of Water Content in Bioethanol Using the 1H NMR Chemical Shift Change

“…Chemical shift in NMR spectrum has been also used in quantitative analysis because it is affected by the physico‐chemical properties of the environment. Various quantities including solution temperature, pH, molecular p K a values, and chemical kinetics have been determined by measuring the chemical shift changes. Recently, a water content measurement technique based on chemical shift difference was developed .…”