Application of Parahydrogen Induced Polarization Techniques in NMR Spectroscopy and Imaging

Magnetic resonance provides a versatile platform that allows scientists to examine many different types of phenomena. However, the sensitivity of both NMR spectroscopy and MRI is low because the detected signal strength depends on the population difference that exists between the probed nuclear spin states in a magnetic field. This population difference increases with the strength of the interacting magnetic field and decreases with measurement temperature. In contrast, hyperpolarization methods that chemically introduce parahydrogen (a spin isomer of hydrogen with antiparallel spins that form a singlet) based on the traditional parahydrogen induced polarization (PHIP) approach tackle this sensitivity problem with dramatic results. In recent years, the potential of this method for MRI has been recognized, and its impact on medical diagnosis is starting to be realized. In this Account, we describe the use of parahydrogen to hyperpolarize a suitable substrate. This process normally involves the introduction of a molecule of parahydrogen into a target to create large population differences between nuclear spin states. The reaction of parahydrogen breaks the original magnetic symmetry and overcomes the selection rules that prevent both NMR observation and parahydrogen/orthohydrogen interconversion, yielding access to the normally invisible hyperpolarization associated with parahydrogen. Therefore the NMR or MRI measurement delivers a marked increase in the detected signal strength over the normal Boltzmann-population derived result. Consequently, measurements can be made which would otherwise be impossible. This approach was pioneered by Weitekamp, Bargon, and Eisenberg, in the late 1980s. Since 1993, we have used this technique in York to study reaction mechanisms and to characterize normally invisible inorganic species. We also describe signal amplification by reversible exchange (SABRE), an alternative route to sensitize molecules without directly incorporating a molecule of parahydrogen. This approach widens the applicability of PHIP methods and the range of materials that can be hyperpolarized. In this Account we describe our parahydrogen studies in York over the last 20 years and place them in a wider context. We describe the characterization of organometallic reaction intermediates including those involved in catalytic reactions, either with or without hydride ligands. The collection of spectroscopic and kinetic data with rapid inverse detection methods has proved to be particularly informative. We can see enhanced signals for the organic products of catalytic reactions that are linked directly to the catalytic intermediates that form them. This method can therefore prove unequivocally that a specific metal complex is involved in a catalytic cycle, thus pinpointing the true route to catalysis. Studies where a pure nuclear spin state is detected show that it is possible to detect all of the analyte molecules present in a sample using NMR. In addition, we describe methods that achieve the selective detection of these enhanced signals, when set against a strong NMR background such as that of water.