Category Archives: SABRE

Zero-field nuclear magnetic resonance of chemically exchanging systems

Barskiy, Danila A., Michael C. D. Tayler, Irene Marco-Rius, John Kurhanewicz, Daniel B. Vigneron, Sevil Cikrikci, Ayca Aydogdu, et al. “Zero-Field Nuclear Magnetic Resonance of Chemically Exchanging Systems.” Nature Communications 10, no. 1 (December 2019): 3002.

https://doi.org/10.1038/s41467-019-10787-9.

Zero- to ultralow-field (ZULF) nuclear magnetic resonance (NMR) is an emerging tool for precision chemical analysis. In this work, we study dynamic processes and investigate the influence of chemical exchange on ZULF NMR J-spectra. We develop a computational approach that allows quantitative calculation of J-spectra in the presence of chemical exchange and apply it to study aqueous solutions of [15N]ammonium (15NHfl4 ) as a model system. We show that pH-dependent chemical exchange substantially affects the J-spectra and, in some cases, can lead to degradation and complete disappearance of the spectral features. To demonstrate potential applications of ZULF NMR for chemistry and biomedicine, we show a ZULF NMR spectrum of [2-13C]pyruvic acid hyperpolarized via dissolution dynamic nuclear polarization (dDNP). We foresee applications of affordable and scalable ZULF NMR coupled with hyperpolarization to study chemical exchange phenomena in vivo and in situations where high-field NMR detection is not possible to implement.

Quantifying the effects of quadrupolar sinks via 15N relaxation dynamics in metronidazoles hyperpolarized via SABRE-SHEATH

Birchall, Jonathan R., Mohammad S. H. Kabir, Oleg G. Salnikov, Nikita V. Chukanov, Alexandra Svyatova, Kirill V. Kovtunov, Igor V. Koptyug, et al. “Quantifying the Effects of Quadrupolar Sinks via 15N Relaxation Dynamics in Metronidazoles Hyperpolarized via SABRE-SHEATH.” Chemical Communications 56, no. 64 (2020): 9098–9101.

https://doi.org/10.1039/D0CC03994B

15N spin–lattice relaxation dynamics in metronidazole-15N3 and metronidazole-15N2 isotopologues are studied for rational design of 15N-enriched biomolecules for signal amplification by reversible exchange in microtesla fields. 15N relaxation dynamics mapping reveals the deleterious effects of interactions with the polarization transfer catalyst and a quadrupolar 14N nucleus within the spin-relayed 15N–15N network.

Hyperpolarization of Nitrile Compounds Using Signal Amplification by Reversible Exchange

Kim, Sarah, Sein Min, Heelim Chae, Hye Jin Jeong, Sung Keon Namgoong, Sangwon Oh, and Keunhong Jeong. “Hyperpolarization of Nitrile Compounds Using Signal Amplification by Reversible Exchange.” Molecules 25, no. 15 (July 23, 2020): 3347.

https://doi.org/10.3390/molecules25153347.

Signal Amplification by Reversible Exchange (SABRE), a hyperpolarization technique, has been harnessed as a powerful tool to achieve useful hyperpolarized materials by polarization transfer from parahydrogen. In this study, we systemically applied SABRE to a series of nitrile compounds, which have been rarely investigated. By performing SABRE in various magnetic fields and concentrations on nitrile compounds, we unveiled its hyperpolarization properties to maximize the spin polarization and its transfer to the next spins. Through this sequential study, we obtained a ~130-fold enhancement for several nitrile compounds, which is the highest number ever reported for the nitrile compounds. Our study revealed that the spin polarization on hydrogens decreases with longer distances from the nitrile group, and its maximum polarization is found to be approximately 70 G with 5 µL of substrates in all structures. Interestingly, more branched structures in the ligand showed less effective polarization transfer mechanisms than the structural isomers of butyronitrile and isobutyronitrile. These first systematic SABRE studies on a series of nitrile compounds will provide new opportunities for further research on the hyperpolarization of various useful nitrile materials.

Analysis of 1-aminoisoquinoline using the signal amplification by reversible exchange hyperpolarization technique #SABRE

Jeong, Hye Jin, Sein Min, and Keunhong Jeong. “Analysis of 1-Aminoisoquinoline Using the Signal Amplification by Reversible Exchange Hyperpolarization Technique.” The Analyst, 2020, 10.1039.D0AN00967A.

https://doi.org/10.1039/D0AN00967A

Signal amplification by reversible exchange (SABRE), a parahydrogen-based hyperpolarization technique, is valuable in detecting low concentrations of chemical compounds, which facilitates the understanding of their functions at molecular level as well as their applicability in nuclear magnetic resonance (NMR) and magentic resource maging (MRI). SABRE of 1- aminoisoquinoline (1-AIQ) is significant because isoquinoline derivatives are the fundamental structures in compounds with notable biological activity and are basic organic building blocks. Through this study, we explain how SABRE is applied to hyperpolarize 1-AIQ for diverse solvent systems such as deuterium and non-deuterium solvents. We observed the amplification of individual protons of 1-AIQ at various magnetic fields. Further, we describe the polarization transfer mechanism of 1-AIQ compared to pyridine using density functional theory (DFT) calculations. These hyperpolarization techniques, including the polarization transfer mechanism investigation on 1-AIQ, will provide a firm basis for the future application of the hyperpolarization study on various bio-friendly materials.

Geminal parahydrogen-induced polarization: accumulating long-lived singlet order on methylene proton pairs #DNPNMR #SABRE

Dagys, Laurynas, Barbara Ripka, Markus Leutzsch, Gamal A. I. Moustafa, James Eills, Johannes F. P. Colell, and Malcolm H. Levitt. “Geminal Parahydrogen-Induced Polarization: Accumulating Long-Lived Singlet Order on Methylene Proton Pairs.” Magnetic Resonance 1, no. 2 (August 7, 2020): 175–86.

https://doi.org/10.5194/mr-1-175-2020

In the majority of hydrogenative parahydrogen-induced polarization (PHIP) experiments, the hydrogen molecule undergoes pairwise cis addition to an unsaturated precursor to occupy vicinal positions on the product molecule. However, some ruthenium-based hydrogenation catalysts induce geminal hydrogenation, leading to a reaction product in which the two hydrogen atoms are transferred to the same carbon centre, forming a methylene (CH2) group. The singlet order of parahydrogen is substantially retained over the geminal hydrogenation reaction, giving rise to a singlet-hyperpolarized CH2 group. Although the T1 relaxation times of the methylene protons are often short, the singlet order has a long lifetime, provided that singlet–triplet mixing is suppressed, either by chemical equivalence of the protons or by applying a resonant radiofrequency field. The long lifetime of the singlet order enables the accumulation of hyperpolarization during the slow hydrogenation reaction. We introduce a kinetic model for the behaviour of the observed hyperpolarized signals, including both the chemical kinetics and the spin dynamics of the reacting molecules. Our work demonstrates the feasibility of producing singlet-hyperpolarized methylene moieties by parahydrogen-induced polarization. This potentially extends the range of molecular agents which may be generated in a hyperpolarized state by chemical reactions of parahydrogen.

Organic Reaction Monitoring of a Glycine Derivative Using Signal Amplification by Reversible Exchange-Hyperpolarized Benchtop Nuclear Magnetic Resonance Spectroscopy #DNPNMR #SABRE

Chae, Heelim, Sein Min, Hye Jin Jeong, Sung Keon Namgoong, Sangwon Oh, Kiwoong Kim, and Keunhong Jeong. “Organic Reaction Monitoring of a Glycine Derivative Using Signal Amplification by Reversible Exchange-Hyperpolarized Benchtop Nuclear Magnetic Resonance Spectroscopy.” Analytical Chemistry 92, no. 16 (August 18, 2020): 10902–7.

https://doi.org/10.1021/acs.analchem.0c01270

Currently, signal amplification by reversible exchange (SABRE) using para-hydrogen is an attractive method of hyperpolarization for overcoming the sensitivity problems of nuclear magnetic resonance (NMR) spectroscopy. Additionally, SABRE, using the spin order of para-hydrogen, can be applied in reaction monitoring processes for organic chemistry reactions where a small amount of reactant exists. The organic reaction monitoring system created by integrating SABRE and benchtop NMR is the ideal combination for monitoring a reaction and identifying the small amounts of materials in the middle of the reaction. We used a laboratory-built setup, prepared materials by synthesis, and showed that the products obtained by esterification of glycine were also active in SABRE. The products, which were synthesized esterified glycine with nicotinoyl chloride hydrochloride, were observed with a reaction monitoring system. The maximum SABRE enhancement among them (approximately 147-fold) validated the use of this method. This study is the first example of the monitoring of this organic reaction by SABRE and benchtop NMR. It will open new possibilities for applying this system to many other organic reactions and also provide more fruitful future applications such as drug discovery and mechanism study.

Automated pneumatic shuttle for magnetic field cycling and parahydrogen hyperpolarized multidimensional NMR

TomHon, Patrick, Evan Akeroyd, Sören Lehmkuhl, Eduard Y. Chekmenev, and Thomas Theis. “Automated Pneumatic Shuttle for Magnetic Field Cycling and Parahydrogen Hyperpolarized Multidimensional NMR.” Journal of Magnetic Resonance 312 (March 2020): 106700.

https://doi.org/10.1016/j.jmr.2020.106700

We present a simple-to-implement pneumatic sample shuttle for automation of magnetic field cycling and multidimensional NMR. The shuttle system is robust allowing automation of hyperpolarized and non-hyperpolarized measurements, including variable field lifetime measurements, SABRE polarization optimization, and SABRE multidimensional experiments. Relaxation-protected singlet states are evaluated by variable-field T1 and TS measurements. Automated shuttling facilitates characterization of hyperpolarization dynamics, field dependence and polarization buildup rates. Furthermore, reproducible hyperpolarization levels at every shuttling event enables automated 2D hyperpolarized NMR, including the first inverse 15N/1H HSQC. We uncover binding mechanisms of the catalytic species through cross peaks that are not accessible in standard one-dimensional hyperpolarized experiments. The simple design of the shuttling setup interfaced with standard TTL signals allows easy adaptation to any standard NMR magnet.

Optimisation of pyruvate hyperpolarisation using SABRE by tuning the active magnetisation transfer catalyst

Tickner, Ben. J., Olga Semenova, Wissam Iali, Peter J. Rayner, Adrian C. Whitwood, and Simon B. Duckett. “Optimisation of Pyruvate Hyperpolarisation Using SABRE by Tuning the Active Magnetisation Transfer Catalyst.” Catalysis Science & Technology 10, no. 5 (2020): 1343–55.

https://doi.org/10.1039/C9CY02498K

Hyperpolarisation techniques such as signal amplification by reversible exchange (SABRE) can deliver NMR signals several orders of magnitude larger than those derived under Boltzmann conditions. SABRE is able to catalytically transfer latent magnetisation from para-hydrogen to a substrate in reversible exchange via temporary associations with an iridium complex. SABRE has recently been applied to the hyperpolarisation of pyruvate, a substrate often used in many in vivo MRI studies. In this work, we seek to optimise the pyruvate-13C2 signal gains delivered through SABRE by fine tuning the properties of the active polarisation transfer catalyst. We present a detailed study of the effects of varying the carbene and sulfoxide ligands on the formation and behaviour of the active [Ir(H)2(η2-pyruvate)(sulfoxide)(NHC)] catalyst to produce a rationale for achieving high pyruvate signal gains in a cheap and refreshable manner. This optimisation approach allows us to achieve signal enhancements of 2140 and 2125-fold for the 1-13C and 2-13C sites respectively of sodium pyruvate-1,2-[13C2].

Progress in low-field benchtop NMR spectroscopy in chemical and biochemical analysis

Grootveld, Martin, Benita Percival, Miles Gibson, Yasan Osman, Mark Edgar, Marco Molinari, Melissa L. Mather, Federico Casanova, and Philippe B. Wilson. “Progress in Low-Field Benchtop NMR Spectroscopy in Chemical and Biochemical Analysis.” Analytica Chimica Acta 1067 (August 2019): 11–30.

https://doi.org/10.1016/j.aca.2019.02.026

The employment of spectroscopically-resolved NMR techniques as analytical probes have previously been both prohibitively expensive and logistically challenging in view of the large sizes of high-field facilities. However, with recent advances in the miniaturisation of magnetic resonance technology, low-field, cryogen-free “benchtop” NMR instruments are seeing wider use. Indeed, these miniaturised spectrometers are utilised in areas ranging from food and agricultural analyses, through to human biofluid assays and disease monitoring. Therefore, it is both intrinsically timely and important to highlight current applications of this analytical strategy, and also provide an outlook for the future, where this approach may be applied to a wider range of analytical problems, both qualitatively and quantitatively. © 2019 Elsevier B.V. All rights reserved.

SABRE: Chemical kinetics and spin dynamics of the formation of hyperpolarization

Barskiy, Danila A., Stephan Knecht, Alexandra V. Yurkovskaya, and Konstantin L. Ivanov. “SABRE: Chemical Kinetics and Spin Dynamics of the Formation of Hyperpolarization.” Progress in Nuclear Magnetic Resonance Spectroscopy 114–115 (October 2019): 33–70.

https://doi.org/10.1016/j.pnmrs.2019.05.005

In this review, we present the physical principles of the SABRE (Signal Amplification By Reversible Exchange) method. SABRE is a promising hyperpolarization technique that enhances NMR signals by transferring spin order from parahydrogen (an isomer of the H2 molecule that is in a singlet nuclear spin state) to a substrate that is to be polarized. Spin order transfer takes place in a transient organometallic complex which binds both parahydrogen and substrate molecules; after dissociation of the SABRE complex, free hyperpolarized substrate molecules are accumulated in solution. An advantage of this method is that the substrate is not modified chemically, and its polarization can be regenerated multiple times by bubbling fresh parahydrogen through the solution. Thus, SABRE requires two key ingredients: (i) polarization transfer and (ii) chemical exchange of both parahydrogen and substrate. While there are several excellent reviews on applications of SABRE, the background of the method is discussed less frequently. In this review we aim to explain in detail how SABRE hyperpolarization is formed, focusing on key aspects of both spin dynamics and chemical kinetics, as well as on the interplay between them. Hence, we first cover the known spin order transfer methods applicable to SABRE — cross-relaxation, coherent spin mixing at avoided level crossings, and coherence transfer — and discuss their practical implementation for obtaining SABRE polarization in the most efficient way. Second, we introduce and explain the principle of SABRE hyperpolarization techniques that operate at ultralow (<1 lT), at low (1lT to 0.1 T) and at high (>0.1 T) magnetic fields. Finally, chemical aspects of SABRE are discussed in detail, including chemical systems that are amenable to SABRE and the exchange processes that are required for polarization formation. A theoretical treatment of the spin dynamics and their interplay with chemical kinetics is also presented. This review outlines known aspects of SABRE and provides guidelines for the design of new SABRE experiments, with the goal of solving practical problems of enhancing weak NMR signals.

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