Non‐Pairwise Interactions in Parahydrogen Experiments: Nuclear Exchange of Single Protons Enables Bulk Water Hyperpolarization

Abstract Hyperpolarization with parahydrogen (p‐H2) is a fast developing field in NMR, which enables overcoming the inherent low sensitivity of this important technique. The hyperpolarization of solvents, particularly of water, offers a wide range of applications for structural investigations of macromolecules and biomedical imaging. Until lately, only organic solvents could be polarized by means of parahydrogen via coherent redistribution of polarization (SABRE mechanism). In this study, we investigate in detail the mechanism of the recently reported bulk water hyperpolarization with a combination of theoretical and experimental methods, finally showing a chemical exchange pathway of single protons as basis for the enhancement. The prerequisites for preserving hyperpolarization upon separation of the two hydrogen atoms of p−H2 are demonstrated by theoretical examinations of the boundary conditions for the hyperpolarization experiments in accordance with the OneH−PHIP theory. These findings yielded the proposal of the novel NEPTUN mechanism (Nuclear Exchange Polarization by Transposing Unattached Nuclei) as the non‐hydrogenative equivalent to the established OneH−PHIP and thus the missing link in parahydrogen hyperpolarization theory.