Improving the Hyperpolarization of ³¹P 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 <i>para</i>hydrogen 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

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 <i>para</i>-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-<i>d</i>₂₂, 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-<i>h</i>₅)­(pyridine-<i>d</i>₅)­(IMes)­(PPh₃)]­BF₄ is examined, its hydride ligand signals are shown to become visible through <i>para</i>-hydrogen-induced polarization rather than SABRE

Utilization of SABRE-Derived Hyperpolarization To Detect Low-Concentration Analytes via 1D and 2D NMR Methods

The characterization of materials by the inherently insensitive method of NMR spectroscopy plays a vital role in chemistry. Increasingly, hyperpolarization is being used to address the sensitivity limitation. Here, by reference to quinoline, we illustrate that the SABRE hyperpolarization technique, which uses <i>para</i>-hydrogen as the source of polarization, enables the rapid completion of a range of NMR measurements. These include the collection of ¹³C, ¹³C­{¹H}, and NOE data in addition to more complex 2D COSY, ultrafast 2D COSY and 2D HMBC spectra. The observations are made possible by the use of a flow probe and external sample preparation cell to re-hyperpolarize the substrate between transients, allowing repeat measurements to be made within seconds. The potential benefit of the combination of SABRE and 2D NMR methods for rapid characterization of low-concentration analytes is therefore established

Iridium N-Heterocyclic Carbene Complexes as Efficient Catalysts for Magnetization Transfer from <i>para</i>-Hydrogen

While the characterization of materials by NMR is hugely important in the physical and biological sciences, it also plays a vital role in medical imaging. This success is all the more impressive because of the inherently low sensitivity of the method. We establish here that [Ir(H)₂(IMes)(py)₃]Cl undergoes both pyridine (py) loss as well as the reductive elimination of H₂. These reversible processes bring <i>para</i>-H₂ and py into contact in a magnetically coupled environment, delivering an 8100-fold increase in ¹H NMR signal strength relative to non-hyperpolarized py at 3 T. An apparatus that facilitates signal averaging has been built to demonstrate that the efficiency of this process is controlled by the strength of the magnetic field experienced by the complex during the magnetization transfer step. Thermodynamic and kinetic data combined with DFT calculations reveal the involvement of [Ir(H)₂(η²-H₂)(IMes)(py)₂]⁺, an unlikely yet key intermediate in the reaction. Deuterium labeling yields an additional 60% improvement in signal, an observation that offers insight into strategies for optimizing this approach