Peter J. Rayner

Strategies for the hyperpolarization of acetonitrile and related ligands by SABRE.

We report on a strategy for using SABRE (signal amplification by reversible exchange) for polarizing 1H and 13C nuclei of weakly interacting ligands which possess biologically relevant and nonaromatic motifs. We first demonstrate this via the polarization of acetonitrile, using Ir(IMes)(COD)Cl as the catalyst precursor, and confirm that the route to hyperpolarization transfer is via the J-coupling network. We extend this work to the polarization of propionitrile, benzylnitrile, benzonitrile, and trans-3-hexenedinitrile in order to assess its generality. In the 1H NMR spectrum, the signal for acetonitrile is enhanced 8-fold over its thermal counterpart when [Ir(H)2(IMes)(MeCN)3]+ is the catalyst. Upon addition of pyridine or pyridine-d5, the active catalyst changes to [Ir(H)2(IMes)(py)2(MeCN)]+ and the resulting acetonitrile 1H signal enhancement increases to 20- and 60-fold, respectively. In 13C NMR studies, polarization transfers optimally to the quaternary 13C nucleus of MeCN while the methyl 13C is hardly polarized. Transfer to 13C is shown to occur first via the 1H–1H coupling between the hydrides and the methyl protons and then via either the 2J or 1J couplings to the respective 13Cs, of which the 2J route is more efficient. These experimental results are rationalized through a theoretical treatment which shows excellent agreement with experiment. In the case of MeCN, longitudinal two-spin orders between pairs of 1H nuclei in the three-spin methyl group are created. Two-spin order states, between the 1H and 13C nuclei, are also created, and their existence is confirmed for Me13CN in both the 1H and 13C NMR spectra using the Only Parahydrogen Spectroscopy protocol.

Iridium(III) hydrido N-heterocyclic carbene-phosphine complexes as catalysts in magnetization transfer reactions.

The hyperpolarization (HP) method signal amplification by reversible exchange (SABRE) uses para-hydrogen to sensitize substrate detection by NMR. The catalyst systems [Ir(H)2(IMes)(MeCN)2(R)]BF4 and [Ir(H)2(IMes)(py)2(R)]BF4 [py = pyridine; R = PCy3 or PPh3; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene], which contain both an electron-donating N-heterocyclic carbene and a phosphine, are used here to catalyze SABRE. They react with acetonitrile and pyridine to produce [Ir(H)2(NCMe)(py)(IMes)(PPh3)]BF4 and [Ir(H)2(NCMe)(py)(IMes)(PCy3)]BF4, complexes that undergo ligand exchange on a time scale commensurate with observation of the SABRE effect, which is illustrated here by the observation of both pyridine and acetonitrile HP. In this study, the required symmetry breaking that underpins SABRE is provided for by the use of chemical inequivalence rather than the previously reported magnetic inequivalence. As a consequence, we show that the ligand sphere of the polarization transfer catalyst itself becomes hyperpolarized and hence that the high-sensitivity detection of a number of reaction intermediates is possible. These species include [Ir(H)2(NCMe)(py)(IMes)(PPh3)]BF4, [Ir(H)2(MeOH)(py)(IMes)(PPh3)]BF4, and [Ir(H)2(NCMe)(py)2(PPh3)]BF4. Studies are also described that employ the deuterium-labeled substrates CD3CN and C5D5N, and the labeled ligands P(C6D5)3 and IMes-d22, to demonstrate that dramatically improved levels of HP can be achieved as a consequence of reducing proton dilution and hence polarization wastage. By a combination of these studies with experiments in which the magnetic field experienced by the sample at the point of polarization transfer is varied, confirmation of the resonance assignments is achieved. Furthermore, when [Ir(H)2(pyridine-h5)(pyridine-d5)(IMes)(PPh3)]BF4 is examined, its hydride ligand signals are shown to become visible through para-hydrogen-induced polarization rather than SABRE.

Preparation and reactions of enantiomerically pure α-functionalized Grignard reagents.

A strategy for the generation of enantiomerically pure α-functionalized chiral Grignard reagents is presented. The approach involves the synthesis of α-alkoxy and α-amino sulfoxides in ≥99:1 dr and ≥99:1 er via asymmetric deprotonation (s-BuLi/chiral diamine) and trapping with Andersens sulfinate (menthol derived). Subsequent sulfoxide → Mg exchange (room temperature, 1 min) and electrophilic trapping delivers a range of enantiomerically pure α-alkoxy and α-amino substituted products. Using this approach, either enantiomer of products can be accessed in 99:1 er from asymmetric deprotonation protocols without the use of (-)-sparteine as the chiral ligand. Two additional discoveries are noteworthy: (i) for the deprotonation and trapping with Andersens sulfinate, there is a lack of stereospecificity at sulfur due to attack of a lithiated intermediate onto the α-alkoxy and α-amino sulfoxides as they form, and (ii) the α-alkoxy-substituted Grignard reagent is configurationally stable at room temperature for 30 min.

Improving the Hyperpolarization of 31 P Nuclei by Synthetic Design

Traditional 31P NMR or MRI measurements suffer from low sensitivity relative to 1H detection and consequently require longer scan times. We show here that hyperpolarization of 31P nuclei through reversible interactions with parahydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold 31P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan 31P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal-to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal-to-noise ratio of just 11.4. 31P-hyperpolarized images are also reported from a 7 T preclinical scanner.

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

Significance The study of molecules and materials is of great significance to both science and human welfare. The noninvasive techniques of NMR and MRI reflect two of the most important methods to study them. However, both of these approaches are insensitive, and hyperpolarization methods to improve sensitivity are needed to access new applications. The hyperpolarization approach signal amplification by reversible exchange is used to produce a signal that is 100,000 times larger than that which would be seen on a routine clinical MRI scanner under Boltzmann equilibrium conditions. By revealing the broad scope of this approach we demonstrate its potential for the future diagnostic detection of metabolites, drugs, and many other small molecules. Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this areas most compelling outcomes. Methods to optimize the low-cost parahydrogen-based approach signal amplification by reversible exchange with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H labeling in both the agent and catalyst and achieve polarization lifetimes of ca. 2 min with 50% polarization in the case of methyl-4,6-d2-nicotinate. Because a 1.5-T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this technique’s generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine, and isonicotinamide analogs that feature as building blocks in biochemistry and many disease-treating drugs.

A Hyperpolarizable 1H Magnetic Resonance Probe for Signal Detection 15 Minutes after Spin Polarization Storage

Abstract Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are two extremely important techniques with applications ranging from molecular structure determination to human imaging. However, in many cases the applicability of NMR and MRI are limited by inherently poor sensitivity and insufficient nuclear spin lifetime. Here we demonstrate a cost‐efficient and fast technique that tackles both issues simultaneously. We use the signal amplification by reversible exchange (SABRE) technique to hyperpolarize the target 1H nuclei and store this polarization in long‐lived singlet (LLS) form after suitable radiofrequency (rf) pulses. Compared to the normal scenario, we achieve three orders of signal enhancement and one order of lifetime extension, leading to 1H NMR signal detection 15 minutes after the creation of the detected states. The creation of such hyperpolarized long‐lived polarization reflects an important step forward in the pipeline to see such agents used as clinical probes of disease.

Molecular MRI in the Earth’s Magnetic Field Using Continuous Hyperpolarization of a Biomolecule in Water

In this work, we illustrate a method to continuously hyperpolarize a biomolecule, nicotinamide, in water using parahydrogen and signal amplification by reversible exchange (SABRE). Building on the preparation procedure described recently by Truong et al. [ J. Phys. Chem. B , 2014 , 118 , 13882 - 13889 ], aqueous solutions of nicotinamide and an Ir-IMes catalyst were prepared for low-field NMR and MRI. The (1)H-polarization was continuously renewed and monitored by NMR experiments at 5.9 mT for more than 1000 s. The polarization achieved corresponds to that induced by a 46 T magnet (P = 1.6 × 10(-4)) or an enhancement of 10(4). The polarization persisted, although reduced, if cell culture medium (DPBS with Ca(2+) and Mg(2+)) or human cells (HL-60) were added, but was no longer observable after the addition of human blood. Using a portable MRI unit, fast (1)H-MRI was enabled by cycling the magnetic field between 5 mT and the Earths field for hyperpolarization and imaging, respectively. A model describing the underlying spin physics was developed that revealed a polarization pattern depending on both contact time and magnetic field. Furthermore, the model predicts an opposite phase of the dihydrogen and substrate signal after one exchange, which is likely to result in the cancelation of some signal at low field.

Using parahydrogen to hyperpolarize amines, amides, carboxylic acids, alcohols, phosphates, and carbonates

Parahydrogen is used to give efficient NMR detection of array of amines, amides, alcohols, carboxylates, carbonates, and phosphates. Hyperpolarization turns weak nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) responses into strong signals, so normally impractical measurements are possible. We use parahydrogen to rapidly hyperpolarize appropriate 1H, 13C, 15N, and 31P responses of analytes (such as NH3) and important amines (such as phenylethylamine), amides (such as acetamide, urea, and methacrylamide), alcohols spanning methanol through octanol and glucose, the sodium salts of carboxylic acids (such as acetic acid and pyruvic acid), sodium phosphate, disodium adenosine 5′-triphosphate, and sodium hydrogen carbonate. The associated signal gains are used to demonstrate that it is possible to collect informative single-shot NMR spectra of these analytes in seconds at the micromole level in a 9.4-T observation field. To achieve these wide-ranging signal gains, we first use the signal amplification by reversible exchange (SABRE) process to hyperpolarize an amine or ammonia and then use their exchangeable NH protons to relay polarization into the analyte without changing its identity. We found that the 1H signal gains reach as high as 650-fold per proton, whereas for 13C, the corresponding signal gains achieved in a 1H-13C refocused insensitive nuclei enhanced by polarization transfer (INEPT) experiment exceed 570-fold and those in a direct-detected 13C measurement exceed 400-fold. Thirty-one examples are described to demonstrate the applicability of this technique.

Illustration of a simple route to generate strong carbon-13 NMR signals that are detectable for several minutes

Abstract Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) suffer from low sensitivity and limited nuclear spin memory lifetimes. Although hyperpolarization techniques increase sensitivity, there is also a desire to increase relaxation times to expand the range of applications addressable by these methods. Here, we demonstrate a route to create hyperpolarized magnetization in 13C nuclear spin pairs that last much longer than normal lifetimes by storage in a singlet state. By combining molecular design and low‐field storage with para‐hydrogen derived hyperpolarization, we achieve more than three orders of signal amplification relative to equilibrium Zeeman polarization and an order of magnitude extension in state lifetime. These studies use a range of specifically synthesized pyridazine derivatives and dimethyl p‐tolyl phenyl pyridazine is the most successful, achieving a lifetime of about 190 s in low‐field, which leads to a 13C‐signal that is visible for 10 minutes.

Direct enhancement of nitrogen-15 targets at high-field by fast ADAPT-SABRE

Graphical abstract