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The present work investigates the potential for enhancing the NMR signals of DNA nucleobases by parahydrogen-based hyperpolarization. Signal amplification by reversible exchange (SABRE) and SABRE in Shield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) of selected DNA nucleobases is demonstrated with the enhancement ( ε ) of 1 H, 15 N, and/or 13 C spins in 3-methyladenine, cytosine, and 6-O-guanine. Solutions of the standard SABRE homogenous catalyst Ir(1,5-cyclooctadeine)(1,3-bis(2,4,6-trimethylphenyl)imidazolium)Cl ("IrIMes") and a given nucleobase in deuterated ethanol/water solutions yielded low 1 H ε values (≤10), likely reflecting weak catalyst binding. However, we achieved natural-abundance enhancement of 15 N signals for 3-methyladenine of ~3300 and ~1900 for the imidazole ring nitrogen atoms. 1 H and 15 N 3-methyladenine studies revealed that methylation of adenine affords preferential binding of the imidazole ring over the pyrimidine ring. Interestingly, signal enhancements ( ε ~240) of both 15 N atoms for doubly labelled cytosine reveal the preferential binding of specific tautomer(s), thus giving insight into the matching of polarization-transfer and tautomerization time scales. 13 C enhancements of up to nearly 50-fold were also obtained for this cytosine isotopomer. These efforts may enable the future investigation of processes underlying cellular function and/or dysfunction, including how DNA nucleobase tautomerization influences mismatching in base-pairing.

In this work the mechanism of methylenecyclobutane hydrogenation over titania-supported Rh, Pt and Pd catalysts was investigated using parahydrogen-induced polarization (PHIP) technique. It was found that methylenecyclobutane hydrogenation leads to formation of a mixture of reaction products including cyclic (1-methylcyclobutene, methylcyclobutane), linear (1-pentene, cis-2-pentene, trans-2-pentene, pentane) and branched (isoprene, 2-methyl-1-butene, 2-methyl-2-butene, isopentane) compounds. Generally, at lower temperatures (150-350 °C) the major reaction product was methylcyclobutane while higher temperature of 450 °C favors the formation of branched products isoprene, 2-methyl-1-butene and 2-methyl-2-butene. PHIP effects were detected for all reaction products except methylenecyclobutane isomers 1-methylcyclobutene and isoprene implying that the corresponding compounds can incorporate two atoms from the same parahydrogen molecule in a pairwise manner in the course of the reaction in particular positions. The mechanisms were proposed for the formation of these products based on PHIP results., (© 2022 Wiley-VCH GmbH.)

Magnetic resonance imaging of [1- 13 C]hyperpolarized carboxylates (most notably, [1- 13 C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of 1 H and 13 C hyperpolarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties using heterogeneous hydrogenation of corresponding vinyl, allyl and propargyl precursors in isotopically unlabeled and 1- 13 C-enriched forms with parahydrogen over Rh/TiO 2 catalysts in methanol-d 4 and in D 2 O. The maximum obtained 1 H polarization was 0.6±0.2 % (for propyl acetate in CD 3 OD), while the highest 13 C polarization was 0.10±0.03 % (for ethyl acetate in CD 3 OD). Hyperpolarization of acetate esters surpassed that of pyruvates, while esters with a triple carbon-carbon bond in unsaturated alcoholic moiety were less efficient as parahydrogen-induced polarization precursors than esters with a double bond. Among the compounds studied, the maximum 1 H and 13 C NMR signal intensities were observed for propyl acetate. Ethyl acetate yielded slightly less intense NMR signals which were dramatically greater than those of other esters under study., (© 2021 Wiley-VCH GmbH.)

We report on a robust and low-cost parahydrogen generator design employing liquid nitrogen as a coolant. The core of the generator consists of catalyst-filled spiral copper tubing, which can be pressurized to 35 atm. Parahydrogen fraction >48% was obtained at 77 K with three nearly identical generators using paramagnetic hydrated iron oxide catalysts. Parahydrogen quantification was performed on the fly via benchtop NMR spectroscopy to monitor the signal from residual orthohydrogen-parahydrogen is NMR silent. This real-time quantification approach was also used to evaluate catalyst activation at up to 1.0 standard liter per minute flow rate. The reported inexpensive device can be employed for a wide range of studies employing parahydrogen as a source of nuclear spin hyperpolarization. To this end, we demonstrate the utility of this parahydrogen generator for hyperpolarization of concentrated sodium [1- 13 C]pyruvate, a metabolic contrast agent under investigation in numerous clinical trials. The reported pilot optimization of SABRE-SHEATH (signal amplification by reversible exchange-shield enables alignment transfer to heteronuclei) hyperpolarization yielded 13 C signal enhancement of over 14,000-fold at a clinically relevant magnetic field of 1 T corresponding to approximately 1.2% 13 C polarization-if near 100% parahydrogen would have been employed, the reported value would be tripled to 13 C polarization of 3.5%.

Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare 15 N-labeled [ 15 N]dalfampridine (4-amino[ 15 N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE-SHEATH technique) with up to 2.0 % 15 N polarization. The 7-hour-long activation of SABRE pre-catalyst [Ir(IMes)(COD)Cl] in the presence of [ 15 N]dalfampridine can be remedied by the use of pyridine co-ligand for catalyst activation while retaining the 15 N polarization levels of [ 15 N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on 15 N polarization levels of free and equatorial catalyst-bound [ 15 N]dalfampridine were investigated. Moreover, we studied 15 N polarization build-up and decay at magnetic field of less than 0.04 μT as well as 15 N polarization decay at the Earth's magnetic field and at 1.4 T., (© 2021 Wiley-VCH GmbH.)

The selectivity of product formation is strongly correlated with the nature of the catalyst active centers. Therefore, the selective synthesis of active sites with certain structure is a big challenge in modern catalysis. Here synthetic procedures are adopted for the formation of 1% Rh/TiO 2 catalysts with different properties. It is shown that the nature of the precursor used for catalyst preparation is important, and that the use of a solution of rhodium acetate instead of rhodium nitrate leads to the selective formation of butenes during 1,3-butadiene hydrogenation. The use of parahydrogen in the reaction results in the enhancement of NMR signals via parahydrogen-induced polarization (PHIP) for all synthesized catalysts, and this signal enhancement increases with increasing catalyst calcination temperature. This effect is explained by the decoration of rhodium nanoparticles with titania which restricts hydrogen mobility on the surface, leading to the highest reported to date selectivity toward the pairwise hydrogen addition route of 7% for supported metal catalysts.

Parahydrogen-induced polarization of 13 C nuclei by side-arm hydrogenation (PHIP-SAH) for [1- 13 C]acetate and [1- 13 C]pyruvate esters with application of PH-INEPT-type pulse sequences for 1 H to 13 C polarization transfer is reported, and its efficiency is compared with that of polarization transfer based on magnetic field cycling (MFC). The pulse-sequence transfer approach may have its merits in some applications because the entire hyperpolarization procedure is implemented directly in an NMR or MRI instrument, whereas MFC requires a controlled field variation at low magnetic fields. Optimization of the PH-INEPT-type transfer sequences resulted in 13 C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1- 13 C]pyruvate and ethyl [1- 13 C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for 1 H to 13 C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1- 13 C]pyruvate and ethyl [1- 13 C]acetate, respectively). Nevertheless, a significant 13 C NMR signal enhancement with respect to thermal polarization allowed us to perform 13 C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications.

Many MRI contrast agents formed with the parahydrogen-induced polarization (PHIP) technique exhibit biocompatible profiles. In the context of respiratory imaging with inhalable molecular contrast agents, the development of nonflammable contrast agents would nonetheless be highly beneficial for the biomedical translation of this sensitive, high-throughput and affordable hyperpolarization technique. To this end, we assess the hydrogenation kinetics, the polarization levels and the lifetimes of PHIP hyperpolarized products (acids, ethers and esters) at various degrees of fluorine substitution. The results highlight important trends as a function of molecular structure that are instrumental for the design of new, safe contrast agents for in vivo imaging applications of the PHIP technique, with an emphasis on the highly volatile group of ethers used as inhalable anesthetics., (© 2020 Wiley-VCH GmbH.)

Nimorazole belongs to the imidazole-based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [ 15 N 3 ]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next-generation MRI-LINAC systems. Herein, we report the first steps to create long-lasting (for tens of minutes) hyperpolarized state on three 15 N sites of [ 15 N 3 ]nimorazole with T 1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000-fold at 1.4 T (corresponding to P 15N of 3.2 %) by 15 N- 15 N spin-relayed SABRE-SHEATH hyperpolarization technique, relying on simultaneous exchange of [ 15 N 3 ]nimorazole and parahydrogen on polarization transfer Ir-IMes catalyst. The presented results pave the way to efficient spin-relayed SABRE-SHEATH hyperpolarization of a wide range of imidazole-based antibiotics and chemotherapeutics., (© 2020 Wiley-VCH GmbH.)

Magnetic resonance imaging (MRI) with the use of hyperpolarized gases as contrast agents provides valuable information on lungs structure and function. While the technology of 129 Xe hyperpolarization for clinical MRI research is well developed, it requires the expensive equipment for production and detection of hyperpolarized 129 Xe. Herein we present the 1 H hyperpolarization of diethyl ether vapor that can be imaged on any clinical MRI scanner. 1 H nuclear spin polarization of up to 1.3 % was achieved using heterogeneous hydrogenation of ethyl vinyl ether with parahydrogen over Rh/TiO 2 catalyst. Liquefaction of diethyl ether vapor proceeds with partial preservation of hyperpolarization and prolongs its lifetime by ≈10 times. The proof-of-principle 2D 1 H MRI of hyperpolarized diethyl ether was demonstrated with 0.1×1.1 mm 2 spatial and 120 ms temporal resolution. The long history of use of diethyl ether for anesthesia is expected to facilitate the clinical translation of the presented approach., (© 2020 Wiley-VCH GmbH.)

The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas-phase lifetimes of hyperpolarized 129 Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of 129 Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low-cost and high-throughput preparation of proton-hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by 1 H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas-phase T 1 relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, with T 1 of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long-lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond., (© 2020 Wiley-VCH GmbH.)

Imaging of gases is a major challenge for any modality including MRI. NMR and MRI signals are directly proportional to the nuclear spin density and the degree of alignment of nuclear spins with applied static magnetic field, which is called nuclear spin polarization. The level of nuclear spin polarization is typically very low, i.e., one hundred thousandth of the potential maximum at 1.5 T and a physiologically relevant temperature. As a result, MRI typically focusses on imaging highly concentrated tissue water. Hyperpolarization methods transiently increase nuclear spin polarizations up to unity, yielding corresponding gains in MRI signal level of several orders of magnitude that enable the 3D imaging of dilute biomolecules including gases. Parahydrogen-induced polarization is a fast, highly scalable, and low-cost hyperpolarization technique. The focus of this Minireview is to highlight selected advances in the field of parahydrogen-induced polarization for the production of hyperpolarized compounds, which can be potentially employed as inhalable contrast agents., (© 2020 Wiley-VCH GmbH.)

We demonstrate that heterogeneous/biphasic chemical reactions can be monitored with high spectroscopic resolution using zero-field nuclear magnetic resonance spectroscopy. This is possible because magnetic susceptibility broadening is negligible at ultralow magnetic fields. We show the two-step hydrogenation of dimethyl acetylenedicarboxylate with para-enriched hydrogen gas in conventional glass NMR tubes, as well as in a titanium tube. The low frequency zero-field NMR signals ensure that there is no significant signal attenuation arising from shielding by the electrically conductive sample container. This method paves the way for in situ monitoring of reactions in complex heterogeneous multiphase systems and in reactors made of conductive materials while maintaining resolution and chemical specificity., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

15 N spin-lattice relaxation dynamics in metronidazole- 15 N 3 and metronidazole- 15 N 2 isotopologues are studied for rational design of 15 N-enriched biomolecules for signal amplification by reversible exchange in microtesla fields. 15 N relaxation dynamics mapping reveals the deleterious effects of interactions with the polarization transfer catalyst and a quadrupolar 14 N nucleus within the spin-relayed 15 N- 15 N network.

We present a pilot quality assurance (QA) study of spin-exchange optical pumping (SEOP) performed on two nearly identical second-generation (GEN-2) automated batch-mode clinical-scale 129 Xe hyperpolarizers, each utilizing a convective forced air oven, high-power (~170 W) continuous pump laser irradiation, and xenon-rich gas mixtures (~1.30 atm partial pressure). In one study, the repeatability of SEOP in a 1000 Torr Xe/900 Torr N 2 /100 Torr 4 He (2000 Torr total pressure) gas mixture is evaluated over the course of ~700 gas loading cycles, with negligible decrease in performance during the first ~200 cycles, and with high 129 Xe polarization levels (avg. %P Xe  = 71.7% with standard deviation σ PXe  = 1.5%), build-up rates (avg. γ SEOP  = 0.019 min -1 with standard deviation σ γ  = 0.003 min -1 ) and polarization lifetimes (avg. T 1  = 90.5 min with standard deviation σ T  = 10.3 min) reported at moderate oven temperature of ~70 °C. Although the SEOP cell in this study exhibited a detectable performance decrease after 400 cycles, the cell continued to produce potentially useable HP 129 Xe with %P Xe  = 42.3 ± 0.6% even after nearly 700 refill cycles. The possibility of "regenerating" "dormant" (i.e., not used for an extended period of time) SEOP cells using repeated temperature cycling methods to recover %P Xe is also demonstrated. The quality and consistency of results show significant promise for translation to clinical-scale production of hyperpolarized 129 Xe contrast agents for imaging and bio-sensing applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We present studies of spin-exchange optical pumping (SEOP) using ternary xenon-nitrogen-helium gas mixtures at high xenon partial pressures (up to 1330 Torr partial pressure at loading, out of 2660 Torr total pressure) in a 500-mL volume SEOP cell, using two automated batch-mode clinical-scale 129 Xe hyperpolarizers operating under continuous high-power (~170 W) pump laser irradiation. In this pilot study, we explore SEOP in gas mixtures with up to 45% 4 He content under a wide range of experimental conditions. When an aluminum jacket cooling/heating design was employed (GEN-3 hyperpolarizer), 129 Xe polarization (%P Xe ) of 55.9 ± 0.9% was observed with mono-exponential build-up rate γ SEOP of 0.049 ± 0.001 min -1 for the 4 He-rich mixture (1000 Torr Xe/900 Torr He, 100 Torr N 2 ), compared to %P Xe of 49.3 ± 3.3% at γ SEOP of 0.035 ± 0.004 min -1 for the N 2 -rich gas mixture (1000 Torr Xe/100 Torr He, 900 Torr N 2 ). When forced-air cooling/heating was used (GEN-2 hyperpolarizer), %P Xe of 83.9 ± 2.7% was observed at γ SEOP of 0.045 ± 0.005 min -1 for the 4 He-rich mixture (1000 Torr Xe/900 Torr He, 100 Torr N 2 ), compared to %P Xe of 73.5 ± 1.3% at γ SEOP of 0.028 ± 0.001 min -1 for the N 2 -rich gas mixture (1000 Torr Xe and 1000 Torr N 2 ). Additionally, %P Xe of 72.6 ± 1.4% was observed at a build-up rate γ SEOP of 0.041 ± 0.003 min -1 for a super-high-density 4 He-rich mixture (1330 Torr Xe/1200 Torr 4 He/130 Torr N 2 ), compared to %P Xe  = 56.6 ± 1.3% at a build-up rate of γ SEOP of 0.034 ± 0.002 min -1 for an N 2 -rich mixture (1330 Torr Xe/1330 Torr N 2 ) using forced air cooling/heating. The observed SEOP hyperpolarization performance under these conditions corresponds to %P Xe improvement by a factor of 1.14 ± 0.04 at 1000 Torr Xe density and by up to a factor of 1.28 ± 0.04 at 1330 Torr Xe density at improved SEOP build-up rates by factors of 1.61 ± 0.18 and 1.21 ± 0.11 respectively. Record %P Xe levels have been obtained here: 83.9 ± 2.7% at 1000 Torr Xe partial pressure and 72.6 ± 1.4% at 1330 Torr Xe partial pressure. In addition to improved thermal stability for SEOP, the use of 4 He-rich gas mixtures also reduces the overall density of produced inhalable HP contrast agents; this property may be desirable for HP 129 Xe inhalation by human subjects in clinical settings-especially in populations with heavily impaired lung function. The described approach should enjoy ready application in the production of inhalable 129 Xe contrast agent with near-unity 129 Xe nuclear spin polarization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Among the hyperpolarization techniques geared toward in vivo magnetic resonance imaging, parahydrogen-induced polarization (PHIP) shows promise due to its low cost and fast speed of contrast agent preparation. The synthesis of 13 C-labeled, unsaturated precursors to perform PHIP by side arm hydrogenation has recently opened new possibilities for metabolic imaging owing to the biological compatibility of the reaction products, although the polarization transfer between the parahydrogen-derived protons and the 13 C heteronucleus must yet be better understood, characterized, and eventually optimized. In this realm, a new experimental strategy incorporating pulse-programmable magnetic field sweeping and in situ detection has been developed. The approach is evaluated by measuring the 13 C polarization of ethyl acetate-1- 13 C, i.e ., the product of pairwise addition of parahydrogen to vinyl acetate-1- 13 C, resulting from zero-crossing magnetic field ramps of various durations, amplitudes, and step sizes. The results demonstrate (i) the profound effect these parameters have on the 1 H to 13 C polarization transfer efficiency and (ii) the high reproducibility of the technique.

Parahydrogen-induced polarization (PHIP) is a powerful technique for studying hydrogenation reactions in gas and liquid phases. Pairwise addition of parahydrogen to the hydrogenation substrate imparts nuclear spin order to reaction products, manifested as enhanced 1H NMR signals from the nascent proton sites. Nanoscale metal catalysts immobilized on supports comprise a promising class of catalysts for producing PHIP effects; however, on such catalysts the percentage of substrates undergoing the pairwise addition route-a necessary condition for observing PHIP-is usually low. In this paper, we present a systematic study of several metal catalysts (Rh, Pt, Pd, and Ir) supported on TiO2 in liquid-phase hydrogenation of different prototypical phenylalkynes (phenylacetylene, 1-phenyl-1-propyne, and 3-phenyl-1-propyne) with parahydrogen. Catalyst activity and selectivity were found to be affected by both the nature of the active metal and the percentage of metal loading. It was demonstrated that the optimal catalyst for production of hyperpolarized products is Rh/TiO2 with 4 wt% metal loading, whereas Pd/TiO2 provided the greatest selectivity for semihydrogenation of phenylalkynes. In a study of liquid-phase hydrogenation reaction kinetics, it was shown that reaction order with respect to hydrogen is nearly the same for pairwise and non-pairwise H2 addition-consistent with a similar nature of the catalytically active sites for these reaction pathways.

A robust medium-scale (approximately 3 g) synthetic method for 15 N labeling of pyridine ( 15 N-Py) is reported based on the Zincke reaction. 15 N enrichment in excess of 81% was achieved with approximately 33% yield. 15 N-Py serves as a standard substrate in a wide range of studies employing a hyperpolarization technique for efficient polarization transfer from parahydrogen to heteronuclei; this technique, called SABRE (signal amplification by reversible exchange), employs a simultaneous chemical exchange of parahydrogen and a to-be-hyperpolarized substrate (e.g., pyridine) on metal centers. In studies aimed at the development of hyperpolarized contrast agents for in vivo molecular imaging, pyridine is often employed either as a model substrate (for hyperpolarization technique development, quality assurance, and phantom imaging studies) or as a co-substrate to facilitate more efficient hyperpolarization of a wide range of emerging contrast agents (e.g., nicotinamide). Here, the produced 15 N-Py was used for the feasibility study of spontaneous 15 N hyperpolarization at high magnetic (HF) fields (7 T and 9.4 T) of an NMR spectrometer and an MRI scanner. SABRE hyperpolarization enabled acquisition of 2D MRI imaging of catalyst-bound 15 N-pyridine with 75 × 75 mm 2 field of view (FOV), 32 × 32 matrix size, demonstrating the feasibility of 15 N HF-SABRE molecular imaging with 2.4 × 2.4 mm 2 spatial resolution., (© 2018 John Wiley & Sons, Ltd.)

Signal Amplification by Reversible Exchange (SABRE) is a promising method for NMR signal enhancement and production of hyperpolarized molecules. As nuclear spin relaxation times of heteronuclei are usually much longer than those of protons, SABRE-based hyperpolarization of heteronuclei in molecules is highly important in the context of biomedical applications. In this work, we demonstrate that the SLIC-SABRE technique can be successfully used to hyperpolarize 15 N nuclei in dalfampridine. The high polarization level of ca. 8 % achieved in this work made it possible to acquire 15 N MR images at natural abundance of the 15 N nuclei for the first time., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report on an extension of the quasi-resonance (QUASR) pulse sequence used for signal amplification by reversible exchange (SABRE), showing that we may target distantly J -coupled 19 F-spins. Polarization transfer from the parahydrogen-derived hydrides to the 19 F nucleus is accomplished via weak five-bond J -couplings using a shaped QUASR radio frequency pulse at a 0.05 T magnetic field. The net result is the direct generation of hyperpolarized 19 F z -magnetization, derived from the parahydrogen singlet order. An accumulation of 19 F polarization on the free ligand is achieved with subsequent repetition of this pulse sequence. The hyperpolarized 19 F signal exhibits clear dependence on the pulse length, irradiation frequency, and delay time in a manner similar to that reported for 15 N QUASR-SABRE. Moreover, the hyperpolarized 19 F signals of 3- 19 F- 14 N-pyridine and 3- 19 F- 15 N-pyridine isotopologues are similar, suggesting that (i) polarization transfer via QUASR-SABRE is irrespective of the nitrogen isotopologue and (ii) the presence or absence of the spin-1/2 15 N nucleus has no impact on the efficiency of QUASR-SABRE polarization transfer. Although optimization of polarization transfer efficiency to 19 F ( P 19 F ≈ 0.1%) was not the goal of this study, we show that high-field SABRE can be efficient and broadly applicable for direct hyperpolarization of 19 F spins.

Supporting two metal binding sites by a tailored polydentate trop-based (trop = 5 H -dibenzo[ a , d ]cyclohepten-5-yl) ligand yields highly unsymmetric homobimetallic rhodium(i) complexes. Their reaction with hydrogen rapidly forms Rh hydrides that undergo an intramolecular semihydrogenation of two C[triple bond, length as m-dash]C bonds of the trop ligand. This reaction is chemoselective and converts C[triple bond, length as m-dash]C bonds to a bridging carbene and an olefinic ligand in the first and the second semihydrogenation steps, respectively. Stabilization by a bridging diphosphine ligand allows characterization of a Rh hydride species by advanced NMR techniques and may provide insight into possible elementary steps of H 2 activation by interfacial sites of heterogeneous Rh/C catalysts., (This journal is © The Royal Society of Chemistry 2019.)

The NMR hyperpolarization of uniformly 15 N-labeled [ 15 N 3 ]metronidazole is demonstrated by using SABRE-SHEATH. In this antibiotic, the 15 NO 2 group is hyperpolarized through spin relays created by 15 N spins in [ 15 N 3 ]metronidazole, and the polarization is transferred from parahydrogen-derived hydrides over six chemical bonds. In less than a minute of parahydrogen bubbling at approximately 0.4 μT, a high level of nuclear spin polarization (P 15N ) of around 16 % is achieved on all three 15 N sites. This product of 15 N polarization and concentration of 15 N spins is around six-fold better than any previous value determined for 15 N SABRE-derived hyperpolarization. At 1.4 T, the hyperpolarized state persists for tens of minutes (relaxation time, T 1 ≈10 min). A novel synthesis of uniformly 15 N-enriched metronidazole is reported with a yield of 15 %. This approach can potentially be used for synthesis of a wide variety of in vivo metabolic probes with potential uses ranging from hypoxia sensing to theranostic imaging., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Magnetic Resonance Imaging (MRI) is a powerful non-invasive diagnostic method extensively used in biomedical studies. A significant limitation of MRI is its relatively low signal-to-noise ratio, which can be increased by hyperpolarizing nuclear spins. One promising method is Signal Amplification By Reversible Exchange (SABRE), which employs parahydrogen as a source of hyperpolarization. Recent studies demonstrated the feasibility to improve MRI sensitivity with this hyperpolarization technique. Hyperpolarized 15 N nuclei in biomolecules can potentially retain their spin alignment for tens of minutes, providing an extended time window for the utilization of the hyperpolarized compounds. In this work, we demonstrate for the first time that radio-frequency-based SABRE hyperpolarization techniques can be used to obtain 15 N MRI of biomolecule 1- 15 N-nicotinamide. Two image acquisition strategies were utilized and compared: Single Point Imaging (SPI) and Fast Low Angle SHot (FLASH). These methods demonstrated opportunities of high-field SABRE for biomedical applications., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

13 C-hyperpolarized carboxylates, such as pyruvate and acetate, are emerging molecular contrast agents for MRI visualization of various diseases, including cancer. Here we present a systematic study of 1 H and 13 C parahydrogen-induced polarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties. It was found that allyl pyruvate is the most efficiently hyperpolarized compound from those under study, yielding 21% and 5.4% polarization of 1 H and 13 C nuclei, respectively, in CD 3 OD solutions. Allyl pyruvate and ethyl acetate were also hyperpolarized in aqueous phase using homogeneous hydrogenation with parahydrogen over water-soluble rhodium catalyst. 13 C polarization of 0.82% and 2.1% was obtained for allyl pyruvate and ethyl acetate, respectively. 13 C-hyperpolarized methanolic and aqueous solutions of allyl pyruvate and ethyl acetate were employed for in vitro MRI visualization, demonstrating the prospects for translation of the presented approach to biomedical in vivo studies.

We report a systematic study of relaxation dynamics of hyperpolarized (HP) propane and HP propane-d 6 prepared by heterogeneous pairwise parahydrogen addition to propylene and propylene-d 6 respectively. Long-lived spin states (LLS) created for these molecules at the low magnetic field of 0.0475 T were employed for this study. The parahydrogen-induced overpopulation of a HP propane LLS decays exponentially with time constant (T LLS ) approximately 3-fold greater than the corresponding T 1 values. Both T LLS and T 1 increase linearly with propane pressure in the range from 1 atm (the most biomedically relevant conditions for pulmonary MRI) to 5 atm. The T LLS value of HP propane gas at 1 atm is ~3 s. Deuteration of the substrate (propylene-d 6 ) yields hyperpolarized propane-d 6 gas with T LLS values approximately 20% shorter than those of hyperpolarized fully protonated propane gas, indicating that deuteration does not benefit the lifetime of the LLS HP state. The use of pH 2 or Xe/N 2 buffering gas during heterogeneous hydrogenation reaction (leading to production of 100% HP propane (no buffering gas) versus 43% HP propane gas (with 57% buffering gas) composition mixtures) results in (i) no significant changes in T 1 , (ii) decrease of T LLS values (by 35±7% and 8±7% respectively); and (iii) an increase of the polarization levels of HP propane gas with a propane concentration decrease (by 1.6±0.1-fold and 1.4±0.1-fold respectively despite the decrease in T LLS , which leads to disproportionately greater polarization losses during HP gas transport). Moreover, we demonstrate the feasibility of HP propane cryo-collection (which can be potentially useful for preparing larger amounts of concentrated HP propane, when buffering gas is employed), and T LLS of liquefied HP propane reaches 14.7 seconds, which is greater than the T LLS value of HP propane gas at any pressure studied. Finally, we have explored the utility of using a partial Spin-Lock Induced Crossing (SLIC) radio frequency (RF) pulse sequence for converting the overpopulated LLS into observable 1 H nuclear magnetization at low magnetic field. We find that (i) the bulk of the overpopulated LLS is retained even when the optimal or near-optimal values of SLIC pulse duration are employed, and (ii) the overpopulated LLS of propane is also relatively immune to strong RF pulses-thereby, indicating that LLS is highly suitable as a spin-polarization reservoir in the context of NMR/MRI detection applications. The presented findings may be useful for improving the levels of polarization of HP propane produced by HET-PHIP via the use of an inert buffer gas; increasing the lifetime of the HP state during preparation and storage; and developing efficient approaches for ultrafast MR imaging of HP propane in the context of biomedical applications of HP propane gas, including its potential use as an inhalable contrast agent.

NMR spectroscopy and imaging (MRI) are two of the most important methods to study structure, function, and dynamics from atom to organism scale. NMR approaches often suffer from an insufficient sensitivity, which, however, can be transiently boosted using hyperpolarization techniques. One of these techniques is parahydrogen-induced polarization, which has been used to produce catalyst-free hyperpolarized propane gas with proton polarization that is 3 orders of magnitude greater than equilibrium thermal polarization at a 1.5 T field of a clinical MRI scanner. Here we show that more than 0.3 L of hyperpolarized propane gas can be produced in 2 s. This production rate is more than an order of magnitude greater than that demonstrated previously, and the reported production rate is comparable to that employed for in-human MRI using HP noble gas (e.g., 129 Xe) produced via a spin exchange optical pumping (SEOP) hyperpolarization technique. We show that high polarization values can be retained despite the significant increase in the production rate of hyperpolarized propane. The enhanced signals of produced hyperpolarized propane gas were revealed by stopped-flow MRI visualization at 4.7 T. Achieving this high production rate enables the future use of this compound (already approved for unlimited use in foods by the corresponding regulating agencies, e.g., FDA in the USA, and more broadly as an E944 food additive) as a new inhalable contrast agent for diagnostic detection via MRI.

Catalysts with well-defined, single, active centers are of great importance and their utilization allows the gap between homo- and heterogeneous catalysis to be bridged and, importantly, the main selectivity problem of heterogeneous catalysis and the main separation challenge of homogeneous catalysis to be overcome. Moreover, the use of single-site catalysts allows the NMR signal to be significantly enhanced through the pairwise addition of two hydrogen atoms from a parahydrogen molecule to an unsaturated substrate. This review covers the fundamentals of the synthesis of single-site catalysts and shows the new aspects of their applications in both modern catalysis and the field of parahydrogen-based hyperpolarization. The different novel aspects of the formation and utilization of single-site catalysts, along with the possibility of NMR signal enhancement observations are described., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Signal Amplification By Reversible Exchange (SABRE) is a new and rapidly developing hyperpolarization technique. The recent discovery of Spin-Lock Induced Crossing SABRE (SLIC-SABRE) showed that high field hyperpolarization transfer techniques developed so far were optimized for singlet spin order that does not coincide with the experimentally produced spin state. Here, we investigated the SLIC-SABRE approach and the most advanced quantitative theoretical SABRE model to date. Our goal is to achieve the highest possible polarization with SLIC-SABRE at high field using the standard SABRE system, IrIMes catalyst with pyridine. We demonstrated the accuracy of the SABRE model describing the effects of various physical parameters such as the amplitude and frequency of the radio frequency field, and the effects of chemical parameters such as the exchange rate constants. By fitting the model to the experimental data, the effective life time of the SABRE complex was estimated, as well as the entropy and enthalpy of the complex-dissociation reaction. We show, for the first time, that this SLIC-SABRE model can be useful for the evaluation of the chemical exchange parameters that are very important for the production of highly polarized contrast agents via SABRE.

We report herein a large-scale (>10 g) synthesis of isotopically enriched 1- 13 C-phosphoenolpyruvate and 1- 13 C-phosphoenolpyruvate-d 2 for application in hyperpolarized imaging technology. The 1- 13 C-phosphoenolpyruvate-d 2 was synthesized with 57% overall yield (over two steps), and >98% 2 H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1- 13 C-phosphoenolpyruvate. These two unsaturated compounds with C=C bonds were employed for parahydrogen-induced polarization via pairwise parahydrogen addition in aqueous medium. We find that deuteration of 1- 13 C-phosphoenolpyruvate resulted in overall increase of 1 H T 1 of nascent hyperpolarized protons (4.30 ± 0.04 s versus 2.06 ± 0.01 s) and 1 H polarization (~2.5% versus ~0.7%) of the resulting hyperpolarized 1- 13 C-phospholactate. The nuclear spin polarization of nascent parahydrogen-derived protons was transferred to 1- 13 C nucleus via magnetic field cycling procedure. The proton T 1 increase in hyperpolarized deuterated 1- 13 C-phospholactate yielded approximately 30% better 13 C polarization compared to non-deuterated hyperpolarized 1- 13 C-phospholactate. Analysis of T 1 relaxation revealed that deuteration of 1- 13 C-phospholactate may have resulted in approximately 3-fold worse H→ 13 C polarization transfer efficiency via magnetic field cycling. Since magnetic field cycling is a key polarization transfer step in the Side-Arm Hydrogenation approach, the presented findings may guide more rationale design of contrast agents using parahydrogen polarization of a broad range of 13 C hyperpolarized contrast agents for molecular imaging employing 13 C MRI. The hyperpolarized 1- 13 C-phospholactate-d 2 is of biomedical imaging relevance because it undergoes in vivo dephosphorylation and becomes 13 C hyperpolarized lactate, which as we show can be detected in the brain using 13 C hyperpolarized MRI; an implication for future imaging of neurodegenerative diseases and dementia.

Hyperpolarized gases revolutionize functional pulmonary imaging. Hyperpolarized propane is a promising emerging contrast agent for pulmonary MRI. Unlike hyperpolarized noble gases, proton-hyperpolarized propane gas can be imaged using conventional MRI scanners with proton imaging capability. Moreover, it is non-toxic odorless anesthetic. Furthermore, propane hyperpolarization can be accomplished by pairwise addition of parahydrogen to propylene. Here, we demonstrate the feasibility of propane hyperpolarization via hydrogenation of cyclopropane with parahydrogen. 1 H propane polarization up to 2.4 % is demonstrated here using 82 % parahydrogen enrichment and heterogeneous Rh/TiO 2 hydrogenation catalyst. This level of polarization is several times greater than that obtained with propylene as a precursor under the same conditions despite the fact that direct pairwise addition of parahydrogen to cyclopropane may also lead to formation of propane with NMR-invisible hyperpolarization due to magnetic equivalence of nascent parahydrogen protons in two CH 3 groups. NMR-visible hyperpolarized propane demonstrated here can be formed only via a reaction pathway involving cleavage of at least one C-H bond in the reactant molecule. The resulting NMR signal enhancement of hyperpolarized propane was sufficient for 2D gradient echo MRI of ∼5.5 mL phantom with 1×1 mm 2 spatial resolution and 64×64 imaging matrix despite relatively low chemical conversion of cyclopropane substrate., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report synthesis of 15 N-3- 19 F-pyridine via Zincke salt formation with the overall 35% yield and 84% 15 N isotopic purity. Hyperpolarization studies of Signal Amplification by Reversible Exchange (SABRE) and SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) were performed to investigate the mechanism of polarization transfer from parahydrogen-derived hydride protons to 19 F nucleus in milli-Tesla and micro-Tesla magnetic field regimes in 15 N-3- 19 F-pyridine and 14 N-3- 19 F-pyridine. We found the mismatch between 15 N and 19 F magnetic field hyperpolarization profiles in the micro-Tesla regime indicating that the spontaneous hyperpolarization process likely happens directly from parahydrogen-derived hydride protons to 19 F nucleus without spin-relaying via 15 N site. In case of SABRE magnetic field regime (milli-Tesla magnetic field range), we found that magnetic field profiles for 1 H and 19 F hyperpolarization are very similar, and 19 F polarization levels are significantly lower than 1 H SABRE polarization levels and lower than 19 F SABRE-SHEATH (i.e. obtained at micro-Tesla magnetic field) polarization levels. Our findings support the hypothesis that in milli-Tesla magnetic field regime, the process of 19 F nuclei hyperpolarization is relayed via protons of substrate, and therefore is very inefficient. These findings are important in the context of improvement of the hyperpolarization hardware and rational design of the hyperpolarized molecular probes.

Magnetic resonance (MR) is one of the most versatile and useful physical effects used for human imaging, chemical analysis, and the elucidation of molecular structures. However, its full potential is rarely used, because only a small fraction of the nuclear spin ensemble is polarized, that is, aligned with the applied static magnetic field. Hyperpolarization methods seek other means to increase the polarization and thus the MR signal. A unique source of pure spin order is the entangled singlet spin state of dihydrogen, parahydrogen (pH 2 ), which is inherently stable and long-lived. When brought into contact with another molecule, this "spin order on demand" allows the MR signal to be enhanced by several orders of magnitude. Considerable progress has been made in the past decade in the area of pH 2 -based hyperpolarization techniques for biomedical applications. It is the goal of this Review to provide a selective overview of these developments, covering the areas of spin physics, catalysis, instrumentation, preparation of the contrast agents, and applications., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a simple and effective method to remove IrIMes homogeneous polarization transfer catalysts from solutions where NMR Signal Amplification By Reversible Exchange (SABRE) has been performed, while leaving intact the substrate's hyperpolarized state. Following microTesla SABRE hyperpolarization of 15 N spins in metronidazole, addition of SiO 2 microparticles functionalized with 3-mercaptopropyl or 2-mercaptoethyl ethyl sulfide moieties provides removal of the catalyst from solution well within the hyperpolarization decay time at 0.3 T ( T 1 >3 mins)-and enabling transfer to 9.4 T for detection of enhanced 15 N signals in the absence of catalyst within the NMR-detection region. Successful catalyst removal from solution is supported by the inability to "re-hyperpolarize" 15 N spins in subsequent attempts, as well as by 1 H NMR and ICP-MS. Record-high 15 N nuclear polarization of up to ~34% was achieved, corresponding to >100,000-fold enhancement at 9.4 T, and approximately 5/6 th of the 15 N hyperpolarization is retained after ~20-second-long purification procedure. Taken together, these results help pave the way for future studies involving in vivo molecular imaging using agents hyperpolarized via rapid and inexpensive parahydrogen-based methods.

Hyperpolarized forms of 1- 13 C-acetates and 1- 13 C-pyruvates are used as diagnostic contrast agents for molecular imaging of many diseases and disorders. Here, we report the synthetic preparation of 1- 13 C isotopically enriched and pure from solvent acetates and pyruvates derivatized with unsaturated ester moiety. The reported unsaturated precursors can be employed for NMR hyperpolarization of 1- 13 C-acetates and 1- 13 C-pyruvates via parahydrogen-induced polarization (PHIP). In this PHIP variant, Side arm hydrogenation (SAH) of unsaturated ester moiety is followed by the polarization transfer from nascent parahydrogen protons to 13 C nucleus via magnetic field cycling procedure to achieve hyperpolarization of 13 C nuclear spins. This work reports the synthesis of PHIP-SAH precursors: vinyl 1- 13 C-acetate (55% yield), allyl 1- 13 C-acetate (70% yield), propargyl 1- 13 C-acetate (45% yield), allyl 1- 13 C-pyruvate (60% yield), and propargyl 1- 13 C-pyruvate (35% yield). Feasibility of PHIP-SAH 13 C hyperpolarization was verified by 13 C NMR spectroscopy: hyperpolarized allyl 1- 13 C-pyruvate was produced from propargyl 1- 13 C-pyruvate with 13 C polarization of ∼3.2% in CD 3 OD and ∼0.7% in D 2 O. 13 C magnetic resonance imaging is demonstrated with hyperpolarized 1- 13 C-pyruvate in aqueous medium., Competing Interests: The authors declare no competing financial interest.

The intensity of NMR signals can be enhanced by several orders of magnitude by using various techniques for the hyperpolarization of different molecules. Such approaches can overcome the main sensitivity challenges facing modern NMR/magnetic resonance imaging (MRI) techniques, whilst hyperpolarized fluids can also be used in a variety of applications in material science and biomedicine. This Focus Review considers the fundamentals of the preparation of hyperpolarized liquids and gases by using dissolution dynamic nuclear polarization (d-DNP) and parahydrogen-based techniques, such as signal amplification by reversible exchange (SABRE) and parahydrogen-induced polarization (PHIP), in both heterogeneous and homogeneous processes. The various new aspects in the formation and utilization of hyperpolarized fluids, along with the possibility of observing NMR signal enhancement, are described., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pd-In/Al 2 O 3 single-site catalyst was able to show high selectivity (up to 98 %) in the gas phase semihydrogenation of propyne. Formation of intermetallic Pd-In compound was studied by XPS during reduction of the catalyst. FTIR-CO spectroscopy confirmed single-site nature of the intermetallic Pd-In phase reduced at high temperature. Utilization of Pd-In/Al 2 O 3 in semihydrogenation of propyne with parahydrogen allowed to produce ≈3400-fold NMR signal enhancement for reaction product propene (polarization=9.3 %), demonstrating the large contribution of pairwise hydrogen addition route. Significant signal enhancement as well as the high catalytic activity of the Pd-In catalyst allowed to acquire 1 H MR images of flowing hyperpolarized propene gas selectively for protons in CH, CH 2 and CH 3 groups. This observation is unique and can be easily transferred to the development of a useful MRI technique for an in situ investigation of selective semihydrogenation in catalytic reactors., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Signal Amplification by Reversible Exchange (SABRE) technique employs exchange with singlet-state parahydrogen to efficiently generate high levels of nuclear spin polarization. Spontaneous SABRE has been shown previously to be efficient in the milli-Tesla and micro-Tesla regimes. We have recently demonstrated that high-field SABRE is also possible, where proton sites of molecules that are able to reversibly coordinate to a metal center can be hyperpolarized directly within high-field magnets, potentially offering the convenience of in situ hyperpolarization-based spectroscopy and imaging without sample shuttling. Here, we show efficient polarization transfer from parahydrogen ( para -H 2 ) to the 15 N atoms of imidazole- 15 N 2 and nicotinamide- 15 N achieved via high-field SABRE (HF-SABRE). Spontaneous transfer of spin order from the para -H 2 protons to 15 N atoms at the high magnetic field of an MRI scanner allows one not only to record enhanced 15 N NMR spectra of in situ hyperpolarized biomolecules, but also to perform imaging using conventional MRI sequences. 2D 15 N MRI of high-field SABRE-hyperpolarized imidazole with spatial resolution of 0.3×0.3 mm 2 at 9.4 T magnetic field and a high signal-to-noise ratio (SNR) of ~99 was demonstrated. We show that 1 H MRI of in situ HF-SABRE hyperpolarized biomolecules ( e.g . imidazole- 15 N 2 ) is also feasible. Taken together, these results show that heteronuclear ( 15 N) and 1 H spectroscopic detection and imaging of high-field-SABRE-hyperpolarized molecules are promising tools for a number of emerging applications.

The hyperpolarization of heteronuclei via signal amplification by reversible exchange (SABRE) was investigated under conditions of heterogeneous catalysis and microtesla magnetic fields. Immobilization of [IrCl(COD)(IMes)], [IMes=1,3-bis(2,4,6-trimethylphenyl), imidazole-2-ylidene; COD=cyclooctadiene] catalyst onto silica particles modified with amine linkers engenders an effective heterogeneous SABRE (HET-SABRE) catalyst that was used to demonstrate a circa 100-fold enhancement of 15 N NMR signals in 15 N-pyridine at 9.4 T following parahydrogen bubbling within a magnetic shield. No 15 N NMR enhancement was observed from the supernatant liquid following catalyst separation, which along with XPS characterization supports the fact that the effects result from SABRE under heterogeneous catalytic conditions. The technique can be developed further for producing catalyst-free agents via SABRE with hyperpolarized heteronuclear spins, and thus is promising for biomedical NMR and MRI applications., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The successful transfer of parahydrogen-induced polarization to 15 N spins using heterogeneous catalysts in aqueous solutions was demonstrated. Hydrogenation of a synthesized unsaturated 15 N-labeled precursor (neurine) with parahydrogen (p-H 2 ) over Rh/TiO 2 heterogeneous catalysts yielded a hyperpolarized structural analog of choline. As a result, 15 N polarization enhancements of over two orders of magnitude were achieved for the 15 N-ethyl trimethyl ammonium ion product in deuterated water at elevated temperatures. Enhanced 15 N NMR spectra were successfully acquired at 9.4 T and 0.05 T. Importantly, long hyperpolarization lifetimes were observed at 9.4 T, with a 15 N T 1 of ~6 min for the product molecules, and the T 1 of the deuterated form exceeded 8 min. Taken together, these results show that this approach for generating hyperpolarized species with extended lifetimes in aqueous, biologically compatible solutions is promising for various biomedical applications., Competing Interests: Notes The authors declare no competing financial interests.

Hyperpolarized (HP) propane produced by the parahydrogen-induced polarization (PHIP) technique has been recently introduced as a promising contrast agent for functional lung magnetic resonance (MR) imaging. However, its short lifetime due to a spin-lattice relaxation time T 1 of less than 1 s in the gas phase is a significant translational challenge for its potential biomedical applications. The previously demonstrated approach for extending the lifetime of the HP propane state through long-lived spin states allows the HP propane lifetime to be increased by a factor of ∼3. Here, we demonstrate that a remarkable increase in the propane hyperpolarization decay time at high magnetic field (7.1 T) can be achieved by its dissolution in deuterated organic solvents (acetone- d 6 or methanol- d 4 ). The approximate values of the HP decay time for propane dissolved in acetone- d 6 are 35.1 and 28.6 s for the CH 2 group and the CH 3 group, respectively (similar values were obtained for propane dissolved in methanol- d 4 ), which are ∼50 times larger than the gaseous propane T 1 value. Furthermore, we show that it is possible to retrieve HP propane from solution to the gas phase with the preservation of hyperpolarization.

Mechanistic insight into the semihydrogenation of 1-butyne and 2-butyne on Cu nanoparticles supported on partially dehydroxylated silica (Cu/SiO 2-700 ) was obtained using parahydrogen. Hydrogenation of 1-butyne over Cu/SiO 2-700 yielded 1-butene with ≥97% selectivity. The surface modification of this catalyst with tricyclohexylphosphine (PCy 3 ) increased the selectivity to 1-butene up to nearly 100%, although at the expense of reduced catalytic activity. Similar trends were observed in the hydrogenation of 2-butyne, where Cu/SiO 2-700 provided a selectivity to 2-butene in the range of 72-100% depending on the reaction conditions, while the catalyst modified with PCy 3 again demonstrated nearly 100% selectivity. Parahydrogen-induced polarization effects observed in hydrogenation reactions catalyzed by copper-based catalysts demonstrate the viability of pairwise hydrogen addition over these catalysts. Contribution of pairwise hydrogen addition to 1-butyne was estimated to be at least 0.2-0.6% for unmodified Cu/SiO 2-700 and ≥2.7% for Cu/SiO 2-700 modified with PCy 3 , highlighting the effect of surface modification with the tricyclohexylphosphine ligand.

When parahydrogen reacts with propylene in low magnetic fields (e.g., 0.05T), the reaction product propane develops an overpopulation of pseudo-singlet nuclear spin states. We studied how the Spin-Lock Induced Crossing (SLIC) technique can be used to convert these pseudo-singlet spin states of hyperpolarized gaseous propane into observable magnetization and to detect 1 H NMR signal directly at 0.05T. The theoretical simulation and experimental study of the NMR signal dependence on B 1 power (SLIC amplitude) exhibits a well-resolved dispersion, which is induced by the spin-spin couplings in the eight-proton spin system of propane. We also measured the exponential decay time constants (T LLSS or T S ) of these pseudo-singlet long-lived spin states (LLSS) by varying the time between hyperpolarized propane production and SLIC detection. We have found that, on average, T S is approximately 3 times longer than the corresponding T 1 value under the same conditions in the range of pressures studied (up to 7.6atm). Moreover, T S may exceed 13s at pressures above 7atm in the gas phase. These results are in agreement with the previous reports, and they corroborate a great potential of long-lived hyperpolarized propane as an inhalable gaseous contrast agent for lung imaging and as a molecular tracer to study porous media using low-field NMR and MRI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nuclear spin polarization can be significantly increased through the process of hyperpolarization, leading to an increase in the sensitivity of nuclear magnetic resonance (NMR) experiments by 4-8 orders of magnitude. Hyperpolarized gases, unlike liquids and solids, can often be readily separated and purified from the compounds used to mediate the hyperpolarization processes. These pure hyperpolarized gases enabled many novel MRI applications including the visualization of void spaces, imaging of lung function, and remote detection. Additionally, hyperpolarized gases can be dissolved in liquids and can be used as sensitive molecular probes and reporters. This Minireview covers the fundamentals of the preparation of hyperpolarized gases and focuses on selected applications of interest to biomedicine and materials science., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Parahydrogen-induced polarization (PHIP) is an NMR hyperpolarization technique that increases nuclear spin polarization by orders of magnitude, and it is particularly well-suited to study hydrogenation reactions. However, the use of high-field NMR spectroscopy is not always possible, especially in the context of potential industrial-scale reactor applications. On the other hand, the direct low-field NMR detection of reaction products with enhanced nuclear spin polarization is challenging due to near complete signal cancellation from nascent parahydrogen protons. We show that hydrogenation products prepared by PHIP can be irradiated with weak (on the order of spin-spin couplings of a few hertz) alternating magnetic field (called Spin-Lock Induced Crossing or SLIC) and consequently efficiently detected at low magnetic field (e.g., 0.05 T used here) using examples of several types of organic molecules containing a vinyl moiety. The detected hyperpolarized signals from several reaction products at tens of millimolar concentrations were enhanced by 10000-fold, producing NMR signals an order of magnitude greater than the background signal from protonated solvents.

The activation and conversion of hydrocarbons is one of the most important challenges in chemistry. Transition-metal ions (V, Cr, Fe, Co, etc.) isolated on silica surfaces are known to catalyze such processes. The mechanisms of these processes are currently unknown but are thought to involve C-H activation as the rate-determining step. Here, we synthesize well-defined Co(II) ions on a silica surface using a metal siloxide precursor followed by thermal treatment under vacuum at 500 °C. We show that these isolated Co(II) sites are catalysts for a number of hydrocarbon conversion reactions, such as the dehydrogenation of propane, the hydrogenation of propene, and the trimerization of terminal alkynes. We then investigate the mechanisms of these processes using kinetics, kinetic isotope effects, isotopic labeling experiments, parahydrogen induced polarization (PHIP) NMR, and comparison with a molecular analog. The data are consistent with all of these reactions occurring by a common mechanism, involving heterolytic C-H or H-H activation via a 1,2 addition across a Co-O bond.

A supported metal catalyst was designed, characterized, and tested for aqueous phase heterogeneous hydrogenation of vinyl acetate with parahydrogen to produce 13 C-hyperpolarized ethyl acetate for potential biomedical applications. The Rh/TiO 2 catalyst with a metal loading of 23.2 wt % produced strongly hyperpolarized 13 C-enriched ethyl acetate-1- 13 C detected at 9.4 T. An approximately 14-fold 13 C signal enhancement was detected using circa 50 % parahydrogen gas without taking into account relaxation losses before and after polarization transfer by magnetic field cycling from nascent parahydrogen-derived protons to 13 C nuclei. This first observation of 13 C PHIP-hyperpolarized products over a supported metal catalyst in an aqueous medium opens up new possibilities for production of catalyst-free aqueous solutions of nontoxic hyperpolarized contrast agents for a wide range of biomolecules amenable to the parahydrogen induced polarization by side arm hydrogenation (PHIP-SAH) approach., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report on a simple approach for efficient NMR proton hyperpolarization of propane using the parahydrogen-induced polarization (PHIP) technique, which yielded ≈6.2 % proton polarization using ≈80 % parahydrogen, a record level achieved with any hyperpolarization technique for propane. Unlike in previously developed approaches designed for continuous-flow operation, where reactants (propene and parahydrogen) are simultaneously loaded for homogeneous or heterogeneous pairwise addition of parahydrogen, here a batch-mode method is applied: propene is first loaded into the catalyst-containing solution, which is followed by homogeneous hydrogenation via parahydrogen bubbling delivered at ≈7.1 atm. The achieved nuclear spin polarization of this contrast agent potentially useful for pulmonary imaging is approximately two orders of magnitude greater than that achieved in the continuous-flow homogeneous catalytic hydrogenation, and a factor of 3-10 more efficient compared to the typical results of heterogeneous continuous-flow hydrogenations., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

1 H MRI of gases can potentially enable functional lung imaging to probe gas ventilation and other functions. In this work, 1 H MR images of hyperpolarized and thermally polarized propane gas were obtained using UTE (ultrashort echo time) pulse sequence. A 2D image of thermally polarized propane gas with ~0.9×0.9 mm 2 spatial resolution was obtained in less than 2 seconds, demonstrating that even non-hyperpolarized hydrocarbon gases can be successfully utilized for conventional proton MRI. The experiments were also performed with hyperpolarized propane gas and demonstrated acquisition of high-resolution multi-slice FLASH 2D images in ca. 510 s and non slice-selective 2D UTE MRI images in ca. 2 s. The UTE approach adopted in this study can be potentially used for medical lung imaging. Furthermore, the possibility to combine UTE with selective suppression of 1 H signals from one of the two gases in a mixture is demonstrated in this MRI study. The latter can be useful for visualizing industrially important processes where several gases may be present, e.g., gas-solid catalytic reactions.

We demonstrate an analytical model for the description of the signal amplification by reversible exchange (SABRE) process. The model relies on a combined analysis of chemical kinetics and the evolution of the nuclear spin system during the hyperpolarization process. The presented model for the first time provides rationale for deciding which system parameters (i.e. J-couplings, relaxation rates, reaction rate constants) have to be optimized in order to achieve higher signal enhancement for a substrate of interest in SABRE experiments.