Larisa M. Kovtunova

Toward production of pure 13C hyperpolarized metabolites using heterogeneous parahydrogen-induced polarization of ethyl[1-13C]acetate

Here, we report the production of 13C-hyperpolarized ethyl acetate via heterogeneously catalyzed pairwise addition of parahydrogen to vinyl acetate over TiO2-supported rhodium nanoparticles, followed by magnetic field cycling. Importantly, the hyperpolarization is demonstrated even at the natural abundance of 13C isotope (ca. 1.1%) along with the easiest separation of the catalyst from the hyperpolarized liquid.

Production of Pure Aqueous 13C‐Hyperpolarized Acetate Via Heterogeneous Parahydrogen‐Induced Polarization

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/TiO2 catalyst with a metal loading of 23.2u2005wtu2009% 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 50u2009% 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.

Aqueous, Heterogeneous para-Hydrogen-Induced 15N Polarization

The successful transfer of para-hydrogen-induced polarization to 15N spins using heterogeneous catalysts in aqueous solutions was demonstrated. Hydrogenation of a synthesized unsaturated 15N-labeled precursor (neurine) with parahydrogen (p-H2) over Rh/TiO2 heterogeneous catalysts yielded a hyperpolarized structural analogue of choline. As a result, 15N polarization enhancements of over 2 orders of magnitude were achieved for the 15N-labeled ethyltrimethylammonium ion product in deuterated water at elevated temperatures. Enhanced 15N NMR spectra were successfully acquired at 9.4 and 0.05 T. Importantly, long hyperpolarization lifetimes were observed at 9.4 T, with a 15N T1 of ∼6 min for the product molecules, and the T1 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.

Mechanistic Insight into the Heterogeneous Hydrogenation of Furan Derivatives with the use of Parahydrogen

Parahydrogen‐induced polarization (PHIP) was shown to be a useful and unique technique to study the mechanisms of catalytic reactions involving hydrogen. In this paper, PHIP was utilized for mechanistic investigation of the gas‐phase hydrogenation of furan, 2,3‐dihydrofuran, and 2,5‐dihydrofuran over titania‐supported Rh, Pd, and Pt catalysts. In the hydrogenation of all three substrates over the Rh/TiO2 catalyst, the PHIP technique revealed the possibility of pairwise addition of two H atoms from the same H2 molecule with the formation of tetrahydrofuran molecules while retaining spin correlation between the added protons. In the hydrogenation of 2,3‐dihydrofuran over the Rh/TiO2 catalyst, PHIP effects were detected not only for tetrahydrofuran but also for the reactant (2,3‐dihydrofuran) at positions 2 and 3 of the heterocyclic ring. Such unexpected results are direct evidence for the pairwise replacement of the hydrogen atoms in 2,3‐dihydorfuran. A probable mechanism for this pairwise replacement includes sequential steps of addition and elimination of hydrogen atoms. In contrast, if the hydrogenation of 2,5‐dihydrofuran was performed over Rh/TiO2, PHIP effects were detected for all protons of 2,3‐dihydrofuran, implying that 2,3‐dihydrofuran could be formed from 2,5‐dihydrofuran not only through isomerization of the C=C bond but also through dehydrogenation of 2,5‐dihydrofuran to furan with subsequent semihydrogenation.

Chemical Exchange Reaction Effect on Polarization Transfer Efficiency in SLIC-SABRE

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.

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.

Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane

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 2.4u2009% is demonstrated here using 82u2009% parahydrogen enrichment and heterogeneous Rh/TiO2 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 CH3 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 ∼5.5u2005mL phantom with 1×1u2005mm2 spatial resolution and 64×64 imaging matrix despite relatively low chemical conversion of cyclopropane substrate.