Branching-Chain Propagation of Parahydrogen-Derived Nuclear Spin Order on a Catalyst Surface.

This study reveals that, when two hydrogen atoms are produced on the surface of a catalyst (e. g., a metal nanoparticle) upon dissociation of a parahydrogen molecule, their initial nuclear spin correlation can propagate in a branching-chain fashion as they diffuse and combine with random H atoms to produce H2 molecules, which subsequently dissociate. This process leads to a gradual dilution of the non-equilibrium nuclear spin order, but the number of involved H atoms that share the spin order becomes larger. These conclusions, confirmed by the spin density matrix calculations, may be relevant in the context of parahydrogen-induced polarization (PHIP) in heterogeneous hydrogenations catalyzed by supported metal catalysts, the observation of which apparently contradicts the accepted non-pairwise mechanism of the addition of hydrogen to an unsaturated substrate over such catalysts. The potential consequences of the reported findings are discussed in the context of PHIP effects and beyond.

15N Hyperpolarization of Metronidazole Antibiotic in Aqueous Media Using Phase-Separated Signal Amplification by Reversible Exchange with Parahydrogen.

Metronidazole is a prospective hyperpolarized MRI contrast agent with potential hypoxia sensing utility for applications in cancer, stroke, neurodegenerative diseases, etc. We demonstrate a pilot procedure for production of ∼30 mM hyperpolarized [15N3]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three 15N sites achieved in less than 2 min. The 15N polarization T1 of ∼12 min is reported for the 15NO2 group at the clinically relevant field of 1.4 T in the aqueous phase, demonstrating a remarkably long lifetime of the hyperpolarized state. The produced aqueous solution of [15N3]metronidazole that contained only ∼100 µM of residual Ir was deemed biocompatible via validation through the MTT colorimetric test for assessing cell metabolic activity using human embryotic kidney HEK293T cells. This low-cost and ultrafast hyperpolarization procedure represents a major advance for the production of a biocompatible HP [15N3]metronidazole (and potentially other hyperpolarized drugs) formulation for MRI sensing applications.

Manipulating stereoselectivity of parahydrogen addition to acetylene to unravel interconversion of ethylene nuclear spin isomers.

Symmetric molecules exist as distinct nuclear spin isomers (NSIMs). A deeper understanding of their properties, including interconversion of different NSIMs, requires efficient techniques for NSIM enrichment. In this work, selective hydrogenation of acetylene with parahydrogen (p-H2) was used to achieve the enrichment of ethylene NSIMs and to study their equilibration processes. The effect of the stereoselectivity of H2 addition to acetylene on the imbalance of ethylene NSIMs was experimentally demonstrated by using three different heterogeneous catalysts (an immobilized Ir complex and two supported Pd catalysts). The interconversion of NSIMs with time during ethylene storage was studied using NMR spectroscopy by reacting ethylene with bromine water, which rendered the p-H2-derived protons in the produced 2-bromoethan(2H)ol (BrEtOD) magnetically inequivalent, thereby revealing the non-equilibrium nuclear spin order of ethylene. A thorough analysis of the shape and transformation of the 1H NMR spectra of hyperpolarized BrEtOD allowed us to reveal the initial distribution of produced ethylene NSIMs and their equilibration processes. Comparison of the results obtained with three different catalysts was key to properly attributing the derived characteristic time constants to different ethylene NSIM interconversion processes: ∼3-6 s for interconversion between NSIMs with the same inversion symmetry (i.e., within g or u manifolds) and ∼1700-2200 s between NSIMs with different inversion symmetries (i.e., between g and u manifolds).

Hyperpolarized long-lived spin state of methylene protons of 2-bromoethanol obtained from ethylene with non-equilibrium nuclear spin order.

In this work we achieve a significant overpopulation (PLLS≈1%) of the long-lived spin state (LLS) of methylene protons in 2-bromoethan(2H)ol (BrEtOD) obtained in a reaction between ethylene with non-equilibrium nuclear spin order and bromine water. Given all protons in ethylene are magnetically equivalent, its nuclear states are classified into nuclear spin isomers (NSIM) with total spin I = 2,1,0. Addition of parahydrogen to acetylene produces ethylene with a population of only those NSIMs with I = 1,0. As a result of the reaction with bromine water the non-equilibrium spin order of ethylene is partly transferred to the singlet LLS involving the two methylene groups of BrEtOD. The 1H NMR signal enhancement (SE≈200) obtained as a result of the LLS readout is approximately equal to the SE of the hyperpolarized BrEtOD obtained with a single π/4 pulse. The LLS relaxation time (TLLS) was shown to be approximately 40 s (≈8T1) in the argon-bubbled sample.

Combined homogeneous and heterogeneous hydrogenation to yield catalyst-free solutions of parahydrogen-hyperpolarized [1-13C]succinate.

We show that catalyst-free aqueous solutions of hyperpolarized [1-13C]succinate can be produced using parahydrogen-induced polarization (PHIP) and a combination of homogeneous and heterogeneous catalytic hydrogenation reactions. We generate hyperpolarized [1-13C]fumarate via PHIP using para-enriched hydrogen gas with a homogeneous ruthenium catalyst, and subsequently remove the toxic catalyst and reaction side products via a purification procedure. Following this, we perform a second hydrogenation reaction using normal hydrogen gas to convert the fumarate into succinate using a solid Pd/Al2O3 catalyst. This inexpensive polarization protocol has a turnover time of a few minutes, and represents a major advance for in vivo applications of [1-13C]succinate as a hyperpolarized contrast agent.

Mechanisms of Methylenecyclobutane Hydrogenation over Supported Metal Catalysts Studied by Parahydrogen-Induced Polarization Technique.

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.

Heterogeneous Catalysis and Parahydrogen-Induced Polarization.

Parahydrogen-induced polarization with heterogeneous catalysts (HET-PHIP) has been a subject of extensive research in the last decade since its first observation in 2007. While NMR signal enhancements obtained with such catalysts are currently below those achieved with transition metal complexes in homogeneous hydrogenations in solution, this relatively new field demonstrates major prospects for a broad range of advanced fundamental and practical applications, from providing catalyst-free hyperpolarized fluids for biomedical magnetic resonance imaging (MRI) to exploring mechanisms of industrially important heterogeneous catalytic processes. This review covers the evolution of the heterogeneous catalysts used for PHIP observation, from metal complexes immobilized on solid supports to bulk metals and single-atom catalysts and discusses the general visions for maximizing the obtained NMR signal enhancements using HET-PHIP. Various practical applications of HET-PHIP, both for catalytic studies and for potential production of hyperpolarized contrast agents for MRI, are described.

PHIP hyperpolarized [1-13C]pyruvate and [1-13C]acetate esters via PH-INEPT polarization transfer monitored by 13C NMR and MRI.

Parahydrogen-induced polarization of 13C nuclei by side-arm hydrogenation (PHIP-SAH) for [1-13C]acetate and [1-13C]pyruvate esters with application of PH-INEPT-type pulse sequences for 1H to 13C 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 13C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1-13C]pyruvate and ethyl [1-13C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for 1H to 13C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1-13C]pyruvate and ethyl [1-13C]acetate, respectively). Nevertheless, a significant 13C NMR signal enhancement with respect to thermal polarization allowed us to perform 13C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications.

Mechanistic in situ investigation of heterogeneous hydrogenation over Rh/TiO2 catalysts: selectivity, pairwise route and catalyst nature.

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/TiO2 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.

Pd-based bimetallic catalysts for parahydrogen-induced polarization in heterogeneous hydrogenations.

Production of hyperpolarized catalyst-free gases and liquids by heterogeneous hydrogenation with parahydrogen can be useful for various technical as well as biomedical applications, including in vivo studies, investigations of mechanisms of industrially important catalytic processes, enrichment of nuclear spin isomers of polyatomic gases, and more. In this regard, the wide systematic search for heterogeneous catalysts effective in pairwise H2 addition required for the observation of parahydrogen-induced polarization (PHIP) effects is crucial. Here in this work we demonstrate the competitive advantage of Pd-based bimetallic catalysts for PHIP in heterogeneous hydrogenations (HET-PHIP). The dilution of catalytically active Pd with less active Ag or In atoms provides the formation of atomically dispersed Pd1 sites on the surface of Pd-based bimetallic catalysts, which are significantly more selective toward pairwise H2 addition compared to the monometallic Pd. Furthermore, the choice of the dilution metal (Ag or In) has a pronounced effect on the efficiency of bimetallic catalysts in HET-PHIP, as revealed by comparing Pd-Ag and Pd-In bimetallic catalysts.

Chemical Reaction Monitoring using Zero-Field Nuclear Magnetic Resonance Enables Study of Heterogeneous Samples in Metal Containers.

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.

Single-Site Heterogeneous Catalysts: From Synthesis to NMR Signal Enhancement.

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.

Selective Single-Site Pd-In Hydrogenation Catalyst for Production of Enhanced Magnetic Resonance Signals using Parahydrogen.

Pd-In/Al2 O3 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/Al2 O3 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, CH2 and CH3 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.

Pairwise hydrogen addition in the selective semihydrogenation of alkynes on silica-supported Cu catalysts.

Mechanistic insight into the semihydrogenation of 1-butyne and 2-butyne on Cu nanoparticles supported on partially dehydroxylated silica (Cu/SiO2-700) was obtained using parahydrogen. Hydrogenation of 1-butyne over Cu/SiO2-700 yielded 1-butene with ≥97% selectivity. The surface modification of this catalyst with tricyclohexylphosphine (PCy3) 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/SiO2-700 provided a selectivity to 2-butene in the range of 72-100% depending on the reaction conditions, while the catalyst modified with PCy3 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/SiO2-700 and ≥2.7% for Cu/SiO2-700 modified with PCy3, highlighting the effect of surface modification with the tricyclohexylphosphine ligand.

Extending the Lifetime of Hyperpolarized Propane Gas through Reversible Dissolution.

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 T1 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-d6 or methanol-d4). The approximate values of the HP decay time for propane dissolved in acetone-d6 are 35.1 and 28.6 s for the CH2 group and the CH3 group, respectively (similar values were obtained for propane dissolved in methanol-d4), which are ∼50 times larger than the gaseous propane T1 value. Furthermore, we show that it is possible to retrieve HP propane from solution to the gas phase with the preservation of hyperpolarization.