The theory and practice of hyperpolarization in magnetic resonance using parahydrogen

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Introduction

NMR spectroscopy is arguably the most powerful and versatile analytical spectroscopic method available to analyze nuclides which possess a magnetic dipole moment and, accordingly, spin angular momentum. Moreover, the application of the science and technology of NMR to the medical field in the form of MRI has provided clinicians with a powerful diagnostic tool for patients. However, the lack of sensitivity, associated with not only the number of magnetically-active nuclei present, but also the extent to which the spin angular momenta of those nuclei interact with a magnetic field, is a significant weakness of the technique. Furthermore, as important as MRI is, it suffers from the further weakness that, unlike pulsed NMR spectroscopy, its response is not normally viewed in a frequency specific mode. It is, however, the fact that the nuclei themselves act as barometers of the electronic and molecular environments in which they sit that makes NMR so diagnostic. Paradoxically, perhaps, it is for this reason, together with the non-invasive nature of MRI that makes it so powerful.

Traditionally NMR has dealt with the detection and analysis of nuclear spin angular momentum in a magnetic field at thermal equilibrium. The spin angular moment distribution is viewed as a bulk property of the sample. Thermal energy effects are given by kBT (where kB is the Boltzmann constant) and the population distribution of states is governed by Boltzmann statistics. For spin-1/2 nuclei, whose magnetic states are at thermal equilibrium in a magnetic field, such thermal effects are large compared to the energy difference that exist between the two possible nuclear spin states which arise from the Zeeman splitting. This situation results in broadly equally-populated states such that in a magnetic field of 9.4 T, at 300 K, they exist with a population difference of only 1 in 31,000 for protons.

The intensity of the detected signals is proportional to the magnetogyric ratio (γ) [1] of the nucleus which relates its magnetic dipole moment to its spin angular momentum and ultimately the population difference. Because 1H nuclei occur in ca. 100% natural abundance and possess one of the largest magnetogyric ratios of all NMR-active nuclei, they are actually the easiest to observe by the NMR method. However, there are many other NMR active nuclei, such as 13C, 15N and 31P that commonly occur in organic and organometallic compounds as well as in drugs and biomolecules. These nuclei have lower γ values than 1H, and also may occur in much lower natural abundance, for example 13C at 1.1%. Thus such heteronuclei may only produce signals of weak intensity and in many cases they may not be observable at all, even after averaging to reduce the impact of noise. Signal intensity is also proportional to the square of the magnitude of the static field and hence the development of improved magnet technology has been a common feature of NMR [1]. Not surprisingly, the issue of sensitivity provides a continuous challenge and hence opportunity to NMR spectroscopists, imagers and spectrometer manufacturers alike.

In more recent years, a new form of NMR has emerged that is based on the concept of molecular hyperpolarization. In suitable cases, these methods allow detected signal intensities to be improved by many orders of magnitude. These hyperpolarization techniques, as shown in Fig. 1, include: PHIP [2], [3], [4], [5], DNP [6], [7], [8], [9], [10], NOE [9], [10], [11], CIDNP [12], [13], [14], [15] optical pumping of polarized noble gases [16], [17], [18], ONP [11], [19], EPR pumping, Hartmann–Hahn cross-polarization [20], [21], and Brute-force Nuclear Orientation [22]. The focus of this review is PHIP (parahydrogen induced polarization) and our primary aim is to describe the theory behind the PHIP technique as applied to magnetic resonance, taking into account recent developments and relating theory to its use in chemistry and imaging.

Until recently the range of reactions that could be studied using PHIP methods was limited to those that involved the incorporation of parahydrogen into the molecule of interest. Despite this apparent limitation a huge number of reactions have been investigated and kinetic and mechanistic studies have made good use of the technique. The majority of reaction types that have been studied involve hydrogenation, hydroformylation or hydrosilylation. Further reaction of the hyperpolarized species has also allowed the derivation of mechanistic routes and catalytic cycles. Catalysis and reactions involving complexes based on rhodium, iridium, palladium, ruthenium, platinum and osmium have been investigated to gain insights into the roles of these species [23]. The use of parahydrogen has been discussed and promoted in review articles relating to hydrogenation [24], [25], [26] and catalysis [27] as well as a general review of parahydrogen use in NMR spectroscopy that this article seeks to bring up to date [28]. In a recent development, polarization transfer from parahydrogen has been achieved over short timescales (≈seconds) without the need to incorporate it into the molecule of interest. This method involves the reaction of a catalyst, such as [Ir(COD)(PCy3)(py)][BF4] (where COD is cyclooctadiene and Cy is cyclohexyl), with both pyridine (py) and parahydrogen to form the polarization transfer catalyst, [Ir(H)2(PCy3)(py)3][BF4]. Such signal amplification by reversible exchange (SABRE) in a low magnetic field results in the nuclear spin order transferring from parahydrogen to free pyridine, with observed signal enhancements in 1H, 13C and 15N NMR spectra of greater than 1000-fold. This new development suggests that research with parahydrogen will continue to play an important role in NMR and MRI over the foreseeable future. A review of the ability to control precisely the nuclear spin interactions that give rise to NMR phenomena, which also focuses on the range of applications that would benefit from the increase in sensitivity that using parahydrogen offers, has been published [29].

The main goals of this work are as follows:

  • (i)

    to review the background of parahydrogen, from its discovery to its applications in NMR experiments and the reasons for its usefulness;

  • (ii)

    to summarize in appropriate detail the theory underlying hyperpolarization using parahydrogen, as it currently stands, across a range of applications;

  • (iii)

    to provide an overview of the types of NMR experimental applications to which the PHIP phenomenon has been applied.

Section snippets

The original discoveries, 1986–1988

The existence of two nuclear spin isomers of molecular hydrogen (dihydrogen) was known 60 years before an NMR application for it was discovered [30], [31], [32]. In 1986, Bowers and Weitekamp predicted that the use of parahydrogen-enriched dihydrogen in hydrogenation reactions would result in spin polarization of order unity compared to 10−4 achieved at thermal equilibrium [2]. The bases of their predictions were:

  • (i)

    quantum mechanical symmetry (see Section 4.1 below) mandates that molecular para

Summary of previous reviews on parahydrogen-induced polarization

A number of review papers have been published on PHIP during the last 20 years. The first of these was by Bargon et al. [42], which discussed PHIP in terms of the PASADENA effect and described its similarities to CIDNP. These results are placed in the context of organic synthesis involving catalytic hydrogenation. Fig. 2 illustrates a typical 1H NMR spectrum obtained using this methodology for the hydrogenation of styrene. Experimental methods for both ortho- and parahydrogen enrichment and ortho

The physics of parahydrogen

As referred to earlier, the existence of two forms of molecular hydrogen was proposed in the early days of quantum theory. Indeed, its discovery and explanation is regarded as one the great successes of the new theory. Details of the physics of ortho- and parahydrogen may be found in Farkas’ excellent, albeit somewhat historical, monograph [47], in physical chemistry texts [1] and in statistical mechanics texts such as McQuarrie [48], However, many published papers tend to underplay the physics

Evolution of the nuclear spin singlet state derived from parahydrogen using coupled differential equations

In this Section we look at the evolution of the parahydrogen-derived singlet state immediately after it comes into bonding contact with a substrate of interest but prior to it being placed into high field. We conclude by showing how the resulting state changes in both the PASADENA and ALTADENA experiments. For systems with a small number of spins, sets of coupled differential equations representing the evolution of the product operators under the influence of the Hamiltonian may be set up and

Polarization transfer

The ALTADENA and PASADENA experiments are in essence two extremes of the same hydrogenation experiment, although it is probably fair to say that much of the early work in the area focussed on hydrogenation experiments under PASADENA conditions, perhaps for experimental considerations [69]. Nevertheless, the discussions which follow in Sections 6.1 Transfer under ALTADENA conditions, 6.2 Transfer under PASADENA conditions overlap and should, therefore, be read together rather than in isolation.

High pressure addition and physical shaking

The simplest way to use parahydrogen in an NMR experiment is by filling the headspace above the sample in a sealable NMR tube to a known pressure of parahydrogen gas, shaking the tube in order to dissolve it, and then placing the sample inside the magnet for observation. This provides easy access to both ALTADENA and PASADENA experiments. In the former experiment the reaction with parahydrogen takes place in low magnetic field, whereas in the latter the reaction occurs in the high magnetic

Experimental NMR using parahydrogen

The modification of NMR sequences to interrogate systems that involve parahydrogen may often be achieved by simply replacing a π/2 with a π/4 pulse which produces the optimum detectable response under PASADENA conditions and the 122IzSz initial state (see Section 6.3.1). This approach has been used to generate sequences that are analogous to standard pulse-acquire [2], [5], COSY, HMQC, HSQC and a H-X-H relay experiments [125], [177]. Several versions of the INEPT experiment have been devised

Summary

In this review we have aimed to comprehensively and critically report on the literature descriptions of the polarization transfer and the subsequent evolution of magnetic states resulting from the addition of parahydrogen to inorganic systems and unsaturated organic hydrogen acceptors. In doing so, we have covered evolution under high and low field and thus both the weak and strong coupling regimes. Low field evolution experiments have been shown to generate polarization transfer to coupled

Acknowledgements

We are grateful to the University of York, the ESPRC, the BBSRC, the Wellcome Trust, Consolider-INGENIO 2010, BP Chemicals, SASOL, Astra Zeneca and GlaxoSmithKline UK for financial support. Our thanks are also extended to Bruker BioSpin and Oxford Instruments. We wish to thanks Professor Joachim Bargon and Dr. Johannes Natterer, Professor Daniel Canet and Dr. Sabine Bouguet-Bonnet for helpful discussions. Finally, we wish to acknowledge all the post-graduate students and post-doctoral fellows

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