Kirill V. Kovtunov

NMR Imaging of Catalytic Hydrogenation in Microreactors with the Use of para-Hydrogen

Catalysis is vital to industrial chemistry, and the optimization of catalytic reactors attracts considerable resources. It has proven challenging to correlate the active regions in heterogeneous catalyst beds with morphology and to monitor multistep reactions within the bed. We demonstrate techniques, using magnetic resonance imaging and para-hydrogen (p-H2) polarization, that allow direct visualization of gas-phase flow and the density of active catalyst in a packed-bed microreactor, as well as control over the dynamics of the polarized state in space and time to facilitate the study of subsequent reactions. These procedures are suitable for characterizing reactors and reactions in microfluidic devices where low sensitivity of conventional magnetic resonance would otherwise be the limiting factor.

Observation of Parahydrogen-Induced Polarization in Heterogeneous Hydrogenation on Supported Metal Catalysts†

For homogeneous hydrogenation reactions catalyzed by transition-metal complexes in solution, utilization of the nuclear spin isomers of molecular hydrogen has become an established tool for studies on reaction mechanisms and kinetics. Parahydrogen-induced polarization (PHIP) can enhance the NMR spectroscopy signals of reaction intermediates and products by several orders of magnitude and provides the high sensitivity essential for such studies. It was demonstrated recently that PHIP effects can also be observed in hydrogenation reactions catalyzed by metal complexes immobilized on a solid support. Industrial hydrogenation processes are predominantly heterogeneous and utilize supported metal catalysts. Such catalysts are not expected to produce PHIP effects, since the reaction mechanism involved should destroy the original correlation of the two nuclear spins of parahydrogen. Herein we demonstrate for the first time that, contrary to these expectations, supported metal catalysts such as Pt/Al2O3 and Pd/ Al2O3 do exhibit PHIP effects. This fact can be used for the production of spin-polarized fluids for MRI applications and for developing new research tools for mechanistic and kinetic studies on heterogeneous hydrogenation processes. Homogeneous hydrogenation of unsaturated compounds in solution is often performed with transition metal complexes (e.g., Wilkinson2s catalyst, [RhCl(PPh3)3]). [6] The detailed mechanism of the reaction is fairly well understood. The catalytic cycle (Scheme S1 in the Supporting Information) starts with oxidative addition of an H2 molecule to the metal center to give a metal dihydride species and ends with reductive elimination of the product. Molecular hydrogen is known to be a mixture of two nuclear spin isomers: orthohydrogen with a total nuclear spin of I= 1, and parahydrogen with I= 0. If one of them (usually para-H2) is used in the hydrogenation reaction, pairwise addition of the two hydrogen atoms from the same H2 molecule, ensured by the reaction mechanism, preserves their correlated nuclear spin state. Furthermore, this correlation can strongly enhance NMR signals of the reaction intermediates and products. If hydrogenation is performed in the probe of an NMR spectrometer (i.e., in the high magnetic field of the NMR instrument), two strongly enhanced antiphase multiplets are commonly observed in the H NMR spectrum of the reaction product (Figure S1a). This experimental scheme is known as PASADENA (parahydrogen and synthesis allow dramatic enhancement of nuclear alignment). If hydrogenation is carried out in a low magnetic field and the reaction products are then adiabatically transferred to the NMR magnet for detection, the two multiplets show net signal enhancement of the opposite sign (Figure S1b). This experimental scheme is termed ALTADENA (adiabatic longitudinal transport after dissociation engenders net alignment). The observation of both ALTADENA and PASADENA requires that the two H atoms from the same para-H2 molecule travel as a pair throughout the entire catalytic cycle all the way to the product, and that the time elapsed between initial dissociation of the H2 molecule and formation of the product molecule is not much longer than the nuclear spin relaxation time of the intermediates involved. All this is favored by the fact that all processes take place on a single metal atom of the complex in solution. Since the NMR spectroscopy signal-enhancement factors observed can be as large as several orders of magnitude, hydrogenation with parahydrogen has become a powerful tool for studying the mechanisms and kinetics of homogeneous hydrogenation reactions. Heterogeneous hydrogenation processes often use highly dispersed supported metals (e.g., Pt/Al2O3, Pd/Al2O3) as catalysts. Unlike homogeneous hydrogenation, which takes place on a well-defined single metal center, heterogeneous hydrogenation proceeds over a vast surface of a metal cluster. This gives rise to a large number of interaction possibilities and a variety of relevant and irrelevant species present on the surface during the reaction. As a result, despite a great deal of effort devoted to studying the mechanisms of heterogeneous hydrogenation of simple alkenes such as ethylene, conclusions regarding the reaction mechanism are still controversial. By combining the use of parahydrogen with heterogeneous hydrogenation processes, it may be possible to develop new fundamental and practical applications which rely on the substantial amplification of the NMR signals, such as mechanistic studies of heterogeneous hydrogenation and production of polarized fluids for advanced MRI studies. However, the use of parahydrogen in combination with supported metal catalysts has been postulated to be pointless, [*] K. V. Kovtunov, Prof. Dr. I. V. Koptyug International Tomography Center SB RAS 3A Institutskaya St., Novosibirsk 630090 (Russia) Fax: (+7)383-333-1399 E-mail: koptyug@tomo.nsc.ru

Irreversible Catalyst Activation Enables Hyperpolarization and Water Solubility for NMR Signal Amplification by Reversible Exchange

Activation of a catalyst [IrCl(COD)(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; COD = cyclooctadiene)] for signal amplification by reversible exchange (SABRE) was monitored by in situ hyperpolarized proton NMR at 9.4 T. During the catalyst-activation process, the COD moiety undergoes hydrogenation that leads to its complete removal from the Ir complex. A transient hydride intermediate of the catalyst is observed via its hyperpolarized signatures, which could not be detected using conventional nonhyperpolarized solution NMR. SABRE enhancement of the pyridine substrate can be fully rendered only after removal of the COD moiety; failure to properly activate the catalyst in the presence of sufficient substrate can lead to irreversible deactivation consistent with oligomerization of the catalyst molecules. Following catalyst activation, results from selective RF-saturation studies support the hypothesis that substrate polarization at high field arises from nuclear cross-relaxation with hyperpolarized 1H spins of the hydride/orthohydrogen spin bath. Importantly, the chemical changes that accompanied the catalyst’s full activation were also found to endow the catalyst with water solubility, here used to demonstrate SABRE hyperpolarization of nicotinamide in water without the need for any organic cosolvent—paving the way to various biomedical applications of SABRE hyperpolarization methods.

The Feasibility of Formation and Kinetics of NMR Signal Amplification by Reversible Exchange (SABRE) at High Magnetic Field (9.4 T)

1H NMR signal amplification by reversible exchange (SABRE) was observed for pyridine and pyridine-d5 at 9.4 T, a field that is orders of magnitude higher than what is typically utilized to achieve the conventional low-field SABRE effect. In addition to emissive peaks for the hydrogen spins at the ortho positions of the pyridine substrate (both free and bound to the metal center), absorptive signals are observed from hyperpolarized orthohydrogen and Ir-complex dihydride. Real-time kinetics studies show that the polarization build-up rates for these three species are in close agreement with their respective 1H T1 relaxation rates at 9.4 T. The results suggest that the mechanism of the substrate polarization involves cross-relaxation with hyperpolarized species in a manner similar to the spin-polarization induced nuclear Overhauser effect. Experiments utilizing pyridine-d5 as the substrate exhibited larger enhancements as well as partial H/D exchange for the hydrogen atom in the ortho position of pyridine and concomitant formation of HD molecules. While the mechanism of polarization enhancement does not explicitly require chemical exchange of hydrogen atoms of parahydrogen and the substrate, the partial chemical modification of the substrate via hydrogen exchange means that SABRE under these conditions cannot rigorously be referred to as a non-hydrogenative parahydrogen induced polarization process.

Parahydrogen-induced polarization in heterogeneous catalytic processes.

Parahydrogen-induced polarization of nuclear spins provides enhancements of NMR signals for various nuclei of up to four to five orders of magnitude in magnetic fields of modern NMR spectrometers and even higher enhancements in low and ultra-low magnetic fields. It is based on the use of parahydrogen in catalytic hydrogenation reactions which, upon pairwise addition of the two H atoms of parahydrogen, can strongly enhance the NMR signals of reaction intermediates and products in solution. A recent advance in this field is the demonstration that PHIP can be observed not only in homogeneous hydrogenations but also in heterogeneous catalytic reactions. The use of heterogeneous catalysts for generating PHIP provides a number of significant advantages over the homogeneous processes, including the possibility to produce hyperpolarized gases, better control over the hydrogenation process, and the ease of separation of hyperpolarized fluids from the catalyst. The latter advantage is of paramount importance in light of the recent tendency toward utilization of hyperpolarized substances in in vivo spectroscopic and imaging applications of NMR. In addition, PHIP demonstrates the potential to become a useful tool for studying mechanisms of heterogeneous catalytic processes and for in situ studies of operating catalytic reactors. Here, the known examples of PHIP observations in heterogeneous reactions over immobilized transition metal complexes, supported metals, and some other types of heterogeneous catalysts are discussed and the applications of the technique for hypersensitive NMR imaging studies are presented.

Microfluidic Gas‐Flow Imaging Utilizing Parahydrogen‐Induced Polarization and Remote‐Detection NMR

Microfluidics is the science and technology of systems that process or manipulate small amounts of fluids using channels with dimensions of less than one millimeter. Fluid transport in microfluidic devices is usually monitored by optical detection methods, such as laser-induced fluorescence. Even though they are very useful in many cases, these methods set a limit to the manufacturing material of the chip under study, which must be optically transparent. Furthermore, optical methods generally require addition of markers, which can alter the hydrodynamic properties of the system. Nuclear magnetic resonance (NMR) has several advantages compared with optical methods in microfluidic flow profiling, because it does not require the use of markers, it allows versatile experiments providing image, dynamic, and spectroscopic information, and radiofrequency (RF) waves can penetrate opaque materials. However, conventional NMR measurements using a large coil around the microfluidic device are very challenging or even impossible because of low sensitivity resulting from the low filling factor of the coil (typically on the order of 10 5 to 10 ) and the low sensitivity of large coils. The issue is even worse when gases, whose molecular number density is about three orders of magnitude lower than in liquid, are investigated. Herein, we overcome the sensitivity issue for microfluidic gas flow by combining remote-detection (RD) magnetic resonance imaging (MRI) and parahydrogen-induced polarization (PHIP) techniques. In RD MRI, spatial information is encoded into fluid spins by magnetic field gradients and a large RF coil around the microfluidic device, corresponding to the phase encoding in a conventional MRI experiment. Thereafter, the spin coherences are stored as a longitudinal magnetization, and the amplitude of the magnetization is detected by an ultrasensitive solenoid microcoil outside the device. As the fluid molecules flow from the encoding region to the detector, RD MRI provides time-offlight (TOF) information, making it possible to obtain threedimensional TOF images of fluid flow in the device. In our setup (Figure 1b and Supporting Information), the encoding

Propane-d6 Heterogeneously Hyperpolarized by Parahydrogen.

Long-lived spin states of hyperpolarized propane-d6 gas were demonstrated following pairwise addition of parahydrogen gas to propene-d6 using heterogeneous parahydrogen-induced polarization (HET-PHIP). Hyperpolarized molecules were synthesized using Rh/TiO2 solid catalyst with 1.6 nm Rh nanoparticles. Hyperpolarized (PH ∼ 1%) propane-d6 was detected at high magnetic field (9.4 T) spectroscopically and by high-resolution 3D gradient-echo MRI (4.7 T) as the gas flowed through the radiofrequency coil with a spatial and temporal resolution of 0.5 × 0.5 × 0.5 mm3 and 17.7 s, respectively. Stopped-flow hyperpolarized propane-d6 gas was also detected at 0.0475 T with an observed nuclear spin polarization of PH ∼ 0.1% and a relatively long lifetime with T1,eff = 6.0 ± 0.3 s. Importantly, it was shown that the hyperpolarized protons of the deuterated product obtained via pairwise parahydrogen addition could be detected directly at low magnetic field. Importantly, the relatively long low-field T1,eff of HP propane-d6 gas is not susceptible to paramagnetic impurities as tested by exposure to ∼0.2 atm oxygen. This long lifetime and nontoxic nature of propane gas could be useful for bioimaging applications including potentially pulmonary low-field MRI. The feasibility of high-resolution low-field 2D gradient-echo MRI was demonstrated with 0.88 × 0.88 mm2 spatial and ∼0.7 s temporal resolution, respectively, at 0.0475 T.

High‐Resolution 3D Proton MRI of Hyperpolarized Gas Enabled by Parahydrogen and Rh/TiO2 Heterogeneous Catalyst

Several supported metal catalysts were synthesized, characterized, and tested in heterogeneous hydrogenation of propene with parahydrogen to maximize nuclear spin hyperpolarization of propane gas using parahydrogen induced polarization (PHIP). The Rh/TiO2 catalyst with a metal particle size of 1.6 nm was found to be the most active and effective in the pairwise hydrogen addition and robust, demonstrating reproducible results with multiple hydrogenation experiments and stability for ≥1.5 years. 3D (1) H magnetic resonance imaging (MRI) of 1 % hyperpolarized flowing gas with microscale spatial resolution (625×625×625 μm(3) ) and large imaging matrix (128×128×32) was demonstrated by using a preclinical 4.7 T scanner and 17.4 s imaging scan time.

Long‐Lived Spin States for Low‐Field Hyperpolarized Gas MRI

Parahydrogen induced polarization was employed to prepare a relatively long-lived correlated nuclear spin state between methylene and methyl protons in propane gas. Conventionally, such states are converted into a strong NMR signal enhancement by transferring the reaction product to a high magnetic field in an adiabatic longitudinal transport after dissociation engenders net alignment (ALTADENA) experiment. However, the relaxation time T1 of ∼0.6 s of the resulting hyperpolarized propane is too short for potential biomedical applications. The presented alternative approach employs low-field MRI to preserve the initial correlated state with a much longer decay time TLLSS =(4.7±0.5) s. While the direct detection at low-magnetic fields (e.g. 0.0475 T) is challenging, we demonstrate here that spin-lock induced crossing (SLIC) at this low magnetic field transforms the long-lived correlated state into an observable nuclear magnetization suitable for MRI with sub-millimeter and sub-second spatial and temporal resolution, respectively. Propane is a non-toxic gas, and therefore, these results potentially enable low-cost high-resolution high-speed MRI of gases for functional imaging of lungs and other applications.

NMR Hyperpolarization Techniques of Gases

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.