Application of Parahydrogen Induced Polarization Techniques in NMR Spectroscopy and Imaging

Abstract

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 o...

Delivering strong 1 H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

“…Parahydrogen (p-H 2 ) induced polarization (9) is another hyperpolarization method that is showing great promise (10,11). p-H 2 is a unique hyperpolarized feedstock that has no magnetic moment and is not observable itself.…”

Following palladium catalyzed methoxycarbonylation by hyperpolarized NMR spectroscopy: a parahydrogen based investigation

“…3 For a number of years, the parahydrogen (p-H 2 ) 8 induced polarization (PHIP) 9, 10 effect has been used to yield mechanistic insight into a range of catalytic hydrogenation and hydroformlyation reactions besides monitoring the formation of metal hydride based products. 11,12 These studies employ the PHIP effect to increase the 1 H NMR signal strengths of reaction products that contain protons which were originally located in a molecule of p-H 2 to achieve this goal. The potential signal improvement on a 400 MHz NMR spectrometer, the workhorse of many academic and industrial facilities is dramatic at 32,000-fold and while it has only been reached for one system 13 , when more widely applied the signal gains have still allowed the detection of true reaction intermediates that exist in such low concentrations as to preclude their detection by traditional NMR methods.…”

“…The potential signal improvement on a 400 MHz NMR spectrometer, the workhorse of many academic and industrial facilities is dramatic at 32,000-fold and while it has only been reached for one system 13 , when more widely applied the signal gains have still allowed the detection of true reaction intermediates that exist in such low concentrations as to preclude their detection by traditional NMR methods. 11,14,15 In addition, as PHIP enables the analogous detection of scalar coupled heteronuclei through polarisation transfer, the reliable characterisation of such species is possible 16 and when this approach is coupled with Exchange Spectroscopy (EXSY) experiments their kinetic significance can be determined. [17][18][19][20] Workers have also used this method to examine not only a range of heterogeneous reactions [21][22][23][24][25] but some that don't involve a metal centre.…”

“…[26][27][28][29] The PHIP approach has therefore developed substantially from the early starting point of Weitekamp, 30, 31 Eisenberg 32,33 and Bargon, 34,35 as illustrated in several reviews. 11,12 In order to understand the physical basis of PHIP, p-H 2 needs to be recognised as simply dihydrogen that exists in the anti-symmetric magnetic state that is represented by the nuclear wave function  { . 36 It is easy to prepare, and when a molecule of it is introduced into a reaction product, in high magnetic field, if the two newly formed hydrogen nuclei become chemically distinct then, in the absence of relaxation, they exist initially in two equally populated, and coupled,  and  states.…”

“…Hence, if these nuclei correspond to those of a dihydride product, with two distinct hydride resonances, of dramatically enhanced amplitude, with anti-phase components that are separated by their mutual scalar coupling. 11,30 In contrast, when a monohydride complex is formed indirectly from such a dihydride species it has proven possible to detect its single hydride resonance as an enhanced-emission signal as a consequence of the related One-Proton-PHIP effect described by Eisenberg.…”