Toward Continuous‐Flow Hyperpolarisation of Metabolites via Heterogenous Catalysis, Side‐Arm‐Hydrogenation, and Membrane Dissolution of Parahydrogen

Abstract

Side‐arm hydrogenation (SAH) by homogeneous catalysis has extended the reach of the parahydrogen enhanced NMR technique to key metabolites such as pyruvate. However, homogeneous hydrogenation requires rapid separation of the dissolved catalyst and purification of the hyperpolarised species with a purity sufficient for safe in‐vivo use. An alternate approach is to employ heterogeneous hydrogenation in a continuous‐flow reactor, where separation from the solid catalysts is straightforward. Using a TiO2‐nanorod supported Rh catalyst, we demonstrate continuous‐flow parahydrogen enhanced NMR by heterogeneous hydrogenation of a model SAH precursor, propargyl acetate, at a flow rate of 1.5 mL/min. Parahydrogen gas was introduced into the flowing solution phase using a novel tube‐in‐tube membrane dissolution device. Without much optimization, proton NMR signal enhancements of up to 297 (relative to the thermal equilibrium signals) at 9.4 Tesla were shown to be feasible on allyl‐acetate at a continuous total yield of 33 %. The results are compared to those obtained with the standard batch‐mode technique of parahydrogen bubbling through a suspension of the same catalyst.

Instrumentation for Hydrogenative Parahydrogen-Based Hyperpolarization Techniques

“…The apparatus incorporated a packed-bed catalytic reactor, side arm hydrogenation, and pH 2 membrane dissolution. 17 The polarizer continuously achieved a conversion of 30% and 1 H signal enhancements up to 300 (relative to thermal equilibrium at 9.4 T) were shown to be feasible. However, the polarization transfer to 13 C, side arm cleavage, and transfer to the aqueous phase have yet to be demonstrated.…”

“…While the addition of pH 2 is performed by catalysis at sometimes harsh conditions, a physiological solution devoid of the catalyst is needed for in vivo administration. Various approaches have been described to achieve this goal, including: Filtering homogeneous catalysts, Using immobilized catalysts that remain in the polarizer, − Heterogeneous catalysts that facilitate filtration; ,,− Phase separation and precipitation. ,− …”

“…The lack of such a device may be attributed to the fact that the power and versatility of pH 2 has resulted in quite a few different methods; the magnetic fields alone vary by a factor of 10 9 (from nanotesla to tesla). Even today, pH 2 hyperpolarization methods keep evolving at a fast pace; among the ground-breaking advances, SABRE, gases, , continuous HP, − PHIP-SAH, RASER, − purification methods, and relay methods , are only a few examples from the past decade. These methods require specific experimental conditions and ultimately dedicated instrumentation, which differs from method to method.…”

Interfacing Liquid State Hyperpolarization Methods with NMR Instrumentation

“…Recirculating a liquid between a hyperpolarization chamber for SABRE and a measuring flow cell permits a continuous NMR measurement [ 89 ]. A flow system that mixes para-hydrogen with a steady liquid flow of substrates over a heterogeneous hydrogenation catalyst cartridge can also constantly supply hyperpolarized substrates [ 90 ].…”

A Versatile Compact Parahydrogen Membrane Reactor

“…with hyperpolarization. To address limitations of existing approaches, [13][14][15][16] we advance the use of hollow membranes in our Spin Transfer Automated Reactor (STAR), which features negligible solvent evaporation and enables continuous and automatic operation for days.…”