Relaxation Dispersion NMR to Reveal Fast Dynamics in Brønsted Acid Catalysis: Influence of Sterics and H-Bond Strength on Conformations and Substrate Hopping

[Image: see text] NMR provides both structural and dynamic information, which is key to connecting intermediates and to understanding reaction pathways. However, fast exchanging catalytic intermediates are often inaccessible by conventional NMR due its limited time resolution. Here, we show the combined application of the (1)H off-resonance R(1ρ) NMR method and low temperature (185–175 K) to resolve intermediates exchanging on a μs time scale (ns at room temperature). The potential of the approach is demonstrated on chiral phosphoric acid (CPA) catalysts in their complexes with imines. The otherwise inaccessible exchange kinetics of the E-I ⇌ E-II imine conformations and thermodynamic E-I:E-II imine ratios inside the catalyst pocket are experimentally determined and corroborated by calculations. The E-I ⇌ E-II exchange rate constants (k(ex)(185 K)) for different catalyst–substrate binary complexes varied between 2500 and 19 000 s(–1) (τ(ex) = 500–50 μs). Theoretical analysis of these exchange rate constants revealed the involvement of an intermediary tilted conformation E-III, which structurally resembles the hydride transfer transition state. The main E-I and E-II exchange pathway is a hydrogen bond strength dependent tilting–switching–tilting mechanism via a bifurcated hydrogen bond as a transition state. The reduction in the sterics of the catalyst showed an accelerated switching process by at least an order of magnitude and enabled an additional rotational pathway. Hence, the exchange process is mainly a function of the intrinsic properties of the 3,3′-substituents of the catalyst. Overall, we believe that the present study opens a new dimension in catalysis via experimental access to structures, populations, and kinetics of catalyst–substrate complexes on the μs time scale by the (1)H off-resonance R(1ρ) method.