Probing Self‐Association of (+)‐Catechin Coupled with Hydrogen‐Deuterium Exchange by Solution NMR Spectroscopy

Nuclear magnetic resonance reveals that the rate of hydrogen–deuterium exchange at aromatic C6 and C8 positions of (+)-catechin is accelerated by its reversible self-association. A combined analysis of exchange-induced chemical shifts and relaxation dispersion data characterizes a transient monomer–dimer equilibrium (lifetime ≈ milliseconds) and supports a model where deuteration proceeds up to 170-fold faster in the dimeric state.

Flavan-3-ols, a subclass of flavonoids found in tea, wine, and other plant-derived foods, exhibit potent antioxidant activity and contribute to various health benefits. Their ability to self-associate into supramolecular structures influences their stability, bioavailability, and function in complex matrices. In this study, we investigate the hydrogen–deuterium (H/D) exchange kinetics at the C6 and C8 positions on the A-ring of (+)-catechin, a widely occurring flavan-3-ol, using ¹H nuclear magnetic resonance spectroscopy. At low concentrations, the exchange follows a two-step pseudo-first-order mechanism, with slightly faster deuteration at C6 than at C8 under physiological conditions (298 K, pD 6). Unexpectedly, higher catechin concentrations lead to accelerated exchange rates, not attributable to pD variation but rather to reversible self-association. Through analysis of exchange-induced chemical shift changes (δex)$\left(\delta\right)_{\text{ex}} \left.\right)$, Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion data, and peak intensity time courses, this study characterizes a weak, transient monomer–dimer equilibrium (lifetime ≈ milliseconds). Importantly, the deuteration rate within the dimer is up to 170-fold faster than in the monomer. These findings uncover a previously unrecognized role of transient self-assembly in modulating the reactivity of polyphenols in solution and underscore the relevance of H/D exchange at carbon centers as a sensitive probe for supramolecular dynamics in polyphenolic systems.

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