Using variable field NMR to understand dynamic exchange Jean-Paul Heeb, Craig Butts and Jonathan Clayden University of Bristol, UK Introduction Variable temperature NMR (VTNMR) has long been an established method in small-molecule NMR to study the rate of exchange between nuclei whether through conformational and chemical exchange or ligand binding. Despite the ability to quantify rates and activation barriers, several drawbacks limit the use of this technique across many fields. For example, it cannot easily be applied to systems with narrow windows of temperature activity or stability, such as biological molecules, or those with significant temperature dependent interactions. Discussion In contrast to VTNMR, chemical shift scaling (CSS) allows one to reach a coalescence point, and therefore extract a rate, by only changing the field strength (figure1a vs 1b). 1‑3 In addition, application of CSS in concert with VTNMR enables several coalescence points (at different fields and temperatures) to be observed which in turn leads to Eyring plots with smaller errors and thereby more accurate estimations of enthalpies and entropies of activation, ΔH ‡ and ΔS ‡ (figure 1c & d).
Figure 1. (a) N,N-Dibenzylnaphthamide has four diastereotopic protons of which two coalesce around 50 °C in DMSO-d6 at 500 MHz. (b) Using shift scaling, it is possible to observe a coalescence point at constant temperature (25 °C). (c) Plotting exchange rate against temperature according to the Eyring equation enables the extraction of activation energies – the gradient is proportional to ΔH ‡ and the intercept, ΔS ‡ . Moving away from the coalescence point (the grey arrow), however, gives lower quality data and a higher error in ΔH ‡ and ΔS ‡ (any gradient between the two red lines and any intercept along the orange arrow is possible). (d) More coalescence points (grey arrows, blue data points) decrease the gradient deviation leading to more accurate estimations of ΔH ‡ and ΔS ‡ which can be seen in the smaller deviation of the green lines. Conclusions and future work Using N , N -dibenzylnaphthamide (inset figure 1), we have demonstrated reliable shift scaling to 2% of the original frequency showing a coalescence point at 25 °C and 100 MHz (figure 1b, green spectrum). By varying both the field and temperature as mentioned above, we have obtained several coalescence points and been able to extract activation energies matching that of the literature. 4 Current work is underway to apply CSS to more complex systems, such as biological molecules or dynamic foldamers, and extending to other nuclei. References 1. Ellett, J. D.; et al. Chem. Phys. 51, 2851-2858, 1969.
2. DiVerdi, Joseph A.; et al. J. Chem. Phys. 75, 5594-5595, 1981. 3. Morris, Gareth A.; et al. Chem. Int. Ed. 42, 823-825, 2003. 4. Ahmed, A.; et al. Tetrahedron 54, 13277-13294, 1998.
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