Ralph W. Adams

Reversible interactions with para-hydrogen enhance NMR sensitivity by polarization transfer.

The sensitivity of both nuclear magnetic resonance spectroscopy and magnetic resonance imaging is very low because the detected signal strength depends on the small population difference between spin states even in high magnetic fields. Hyperpolarization methods can be used to increase this difference and thereby enhance signal strength. This has been achieved previously by incorporating the molecular spin singlet para-hydrogen into hydrogenation reaction products. We show here that a metal complex can facilitate the reversible interaction of para-hydrogen with a suitable organic substrate such that up to an 800-fold increase in proton, carbon, and nitrogen signal strengths are seen for the substrate without its hydrogenation. These polarized signals can be selectively detected when combined with methods that suppress background signals.

Iridium N-heterocyclic carbene complexes as efficient catalysts for magnetization transfer from para-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 para-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.

Ultrahigh-Resolution NMR Spectroscopy

All psyched up: A flexible and general pure shift experiment (PSYCHE) has been developed that offers superior sensitivity, spectral purity, and tolerance of strong coupling over existing methods for broadband homonuclear decoupling. The partial spectra of estradiol in [D6]DMSO obtained by normal 1H NMR spectroscopy and PSYCHE are shown for comparison.

Simultaneously Enhancing Spectral Resolution and Sensitivity in Heteronuclear Correlation NMR Spectroscopy

BIRDs eye view: Adding periodic BIRD J-refocusing (BIRD=bilinear rotation decoupling) to data acquisition in an HSQC experiment causes broadband homonuclear decoupling, giving a single signal for each proton chemical shift. This pure shift method improves both resolution and signal-to-noise ratio, without the need for special data processing.

A theoretical basis for spontaneous polarization transfer in non-hydrogenative parahydrogen-induced polarization

When parahydrogen adds to a metal template containing a substrate of interest, the substrate and parahydrogen become coupled, and polarization is shared between the two without the incorporation of the parahydrogen into the substrate. A mechanism for this polarization transfer is presented in which the transfer is propagated through the scalar couplings. At zero field, polarization is transferred between two-, three-, and four-spin zero quantum states, but no single spin magnetization is created. The interplay between the chemical shift evolution and the evolution under scalar coupling at non-zero field generates additional longitudinal spin order and now includes single spin longitudinal z-magnetization. The additional chemical shift interaction introduces a field dependency to the nuclear spin states of the polarized substrate. The net effect of the polarization field strength on the resultant nuclear spin states is shown to be predictable but complex.

Toward Biocompatible Nuclear Hyperpolarization Using Signal Amplification by Reversible Exchange: Quantitative in Situ Spectroscopy and High-Field Imaging

Signal amplification by reversible exchange (SABRE) of a substrate and parahydrogen at a catalytic center promises to overcome the inherent insensitivity of magnetic resonance. In order to apply the new approach to biomedical applications, there is a need to develop experimental equipment, in situ quantification methods, and a biocompatible solvent. We present results detailing a low-field SABRE polarizer which provides well-controlled experimental conditions, defined spins manipulations, and which allows in situ detection of thermally polarized and hyperpolarized samples. We introduce a method for absolute quantification of hyperpolarization yield in situ by means of a thermally polarized reference. A maximum signal-to-noise ratio of ∼103 for 148 μmol of substance, a signal enhancement of 106 with respect to polarization transfer field of SABRE, or an absolute 1H-polarization level of ≈10–2 is achieved. In an important step toward biomedical application, we demonstrate 1H in situ NMR as well as 1H and 13C high-field MRI using hyperpolarized pyridine (d3) and 13C nicotinamide in pure and 11% ethanol in aqueous solution. Further increase of hyperpolarization yield, implications of in situ detection, and in vivo application are discussed.

Foldamer-Mediated Remote Stereocontrol: > 1,60 Asymmetric Induction

An N-terminal L-α-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac6 c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.

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 para-hydrogen as the source of polarization, enables the rapid completion of a range of NMR measurements. These include the collection of (13)C, (13)C{(1)H}, 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.

Diastereomeric ratio determination by high sensitivity band-selective pure shift NMR spectroscopy

An NMR method is reported that allows diastereomeric ratios to be determined even in crowded spectra or where chemical shift differences are small compared to multiplet widths. Band-selective pure shift NMR collapses multiplets to singlets, greatly improving spectral resolution while largely retaining, or even enhancing, signal-to-noise ratio.

Only para-hydrogen spectroscopy (OPSY), a technique for the selective observation of para-hydrogen enhanced NMR signals.

An NMR method is reported for the efficient removal of signals derived from nuclei with thermally equilibrated spin state populations whilst leaving, intact, signals derived from para-hydrogen induced polarisation (PHIP) through gradient assisted coherence selection.