Advancing homogeneous catalysis for parahydrogen-derived hyperpolarisation and its NMR applications

Abstract

Parahydrogen-induced polarisation (PHIP) is a nuclear spin hyperpolarisation technique employed to enhance NMR signals for a wide range of molecules. This is achieved by exploiting the chemical reactions of parahydrogen (para-H₂), the spin-0 isomer of H₂. These reactions break the molecular symmetry of para-H₂ in a way that can produce dramatically enhanced NMR signals for reaction products, and are usually catalysed by a transition metal complex. In this review, we discuss recent advances in novel homogeneous catalysts that can produce hyperpolarised products upon reaction with para-H₂. We also discuss hyperpolarisation attained in reversible reactions (termed signal amplification by reversible exchange, SABRE) and focus on catalyst developments in recent years that have allowed hyperpolarisation of a wider range of target molecules. In particular, recent examples of novel ruthenium catalysts for trans and geminal hydrogenation, metal-free catalysts, iridium sulfoxide-containing SABRE systems, and cobalt complexes for PHIP and SABRE are reviewed. Advances in this catalysis have expanded the types of molecules amenable to hyperpolarisation using PHIP and SABRE, and their applications in NMR reaction monitoring, mechanistic elucidation, biomedical imaging, and many other areas, are increasing.

Fig. 1. (a) Parahydrogen is ‘NMR silent’ and can only be observed by NMR if its symmetry can be broken in a pairwise reaction, often catalysed by a metal centre. Products containing ¹H nuclei that were originally located in para-H₂ can exhibit NMR signals orders-of-magnitude more intense than would be recorded under ‘thermal’ (i.e. Boltzmann) controlled conditions. (b) Under PASADENA conditions, the para-H₂ symmetry-breaking process in a chemical reaction occurs at the spectrometer (high) field and results in population of both the |αβ〉 and |βα〉 nuclear spin energy levels of the product. (c) Under ALTADENA conditions the reaction occurs at Earth's (low) field outside the spectrometer before insertion into the spectrometer for NMR detection. As a result, only one of the |αβ〉 or |βα〉 levels of the product are populated. In this depiction the |αβ〉 state is shown lower in energy and populated. Note that the two protons in the product are assumed to form a weakly coupled AX spin system and the energies are not shown to scale. NMR spectra may show a different appearance when recorded using different flip angles. In these depictions, the population of each state is indicated by the thickness of the line.

Fig. 2. Examples of symmetry-breaking oxidative addition reactions. Formation of hyperpolarised (a) [RhCl(H)₂(PPh₃)₃] upon para-H₂ addition to [RhCl(PPh₃)₃], (b) [IrBr(H)₂CO(PPh₂(CH₂)₂PPh₂)] following para-H₂ addition to [IrBrCO(PPh₂(CH₂)₂PPh₂)] and (c) [IrCO(H)₂I(PPh₃)₂] upon para-H₂ addition to [IrCOI(PPh₃)₂]. Enhanced hydride NMR signals for a minor geometric isomer of [IrCO(H)₂I(PPh₃)₂] are also visible as para-H₂ addition can occur to both symmetry axes of [IrCOI(PPh₃)₂]. Hyperpolarised hydride NMR signals for [Ir(H)₂I(PPh₃)₃], which is formed from CO loss from [IrCO(H)₂I(PPh₃)₂], are also discerned. Adapted from (a) ref. (b) ref. and (c) ref. .

Fig. 3. Examples of PHIP in metal-free para-H₂ activations. (a) ansa-Aminoboranes can activate para-H₂ using a N–B frustrated Lewis pair centre. For example, ¹⁴N- and ¹¹B-decoupled ¹H NMR spectra acquired using QCAT ansa-aminoborane are presented. (b) Pnictogen biradicaloids can also activate para-H₂ and produce PHIP. For instance, a P–P biradicaloid pair where Mes = 2,4,6-trimethylphenyl gives the presented ³¹P NMR spectrum. For comparison, the thermal ³¹P spectrum expanded vertically by a factor of 64 is also shown in the figure. Adapted from (a) ref. and (b) ref. .

Fig. 4. (a) Depiction of the general process of a pairwise hydrogenation reaction. Oxidative addition is the primary step that breaks the symmetry of para-H₂. Subsequent steps such as substrate coordination, hydride migration, and product elimination, yield a hydrogenated product with enhanced ¹H NMR signals. (b) Examples of catalysts reported for early PHIP studies with commercial catalysts commonly used for PHIP today. (c) Example hydrogenation of vinyl acetate to form ethyl acetate, which was used to study the effect of Rh catalyst on factors such as ¹³C polarisation level and conversion to the product. Adapted from ref. . (d) Example water-soluble catalysts reported to produce PHIP in aqueous solutions. (e) Representative examples of ruthenium, palladium and cobalt catalysts used for PHIP.

Fig. 5. (a) Proposed mechanism for the hydrogenation of alkynes, in this example 2-butyne, by ruthenium cyclopentadienyl complexes yielding products that can be hyperpolarised according to traditional PHIP, trans, or geminal PHIP. Adapted from ref. . Similar mechanisms are given in ref. and , although binuclear mechanisms involving two ruthenium centres have also been proposed. (b) Example partial ¹H NMR spectra showing enhanced signals following trans hydrogenation of the indicated alkyne using a ruthenium catalyst. Enhanced ¹H NMR signals for ruthenium carbenes result from geminal hydrogenation. Adapted from ref. . (c) Depiction of metal-catalysed vicinal and geminal exchange in which proton sites on an alkene are exchanged with a metal dihydride. If a dihydride has formed from activation of para-H₂, then this exchange can lead to enhanced ¹H NMR signals for the exchanged sites in the alkene.

Fig. 6. PHIP effects can be observed when nitriles are hydrogenated using para-H₂. The example ¹H NMR spectrum (600 MHz) has been recorded for the reaction mixture shown using a 45° pulse (above) with enhanced imine signals (inset) and a ¹H-OPSY sequence (below) that confirms these protons are derived from para-H₂. Adapted from ref. .

Fig. 7. (a) Mechanism of metal-free hydrogenation and PHIP of alkynes using the ansa-aminoborane HCAT. Notably, para-H₂ protons are split heterolytically and only one of these protons is incorporated into the alkene product. (b) Example ¹H NMR spectrum for an alkene product displaying enhanced ¹H NMR signals for a single proton originating from the para-H₂ feedstock in addition to the NH and BH sites of catalytic intermediates. Adapted from ref. .

Fig. 8. Example oneH-PHIP ¹H NMR spectrum showing polarisation for propanal (lower left) and for iridium hydride intermediates formed during the hydroformylation process (lower right). Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene adapted from ref. .

Fig. 9. Generic depiction of reversible polarisation transfer using SABRE. The symmetry of para-H₂ is broken using a reversible oxidative addition reaction to form a hyperpolarised metal dihydride complex. This catalyses spontaneous polarisation transfer to other ligands (L₁) bound within the complex at low magnetic field (>milliTesla). Auxiliary ligands (L₂), which can be non-exchanging, often play a role in this process where x + y = 4. The iridium complex may be neutral or positively charged depending on the identity of L₁ and L₂ and is often formed in situ.

Fig. 10. Formation of SABRE-active polarisation transfer catalysts from a 16-electron air-stable precatalyst. In this case L represents an auxiliary ligand and Sub a substrate of interest. The charges of the complexes shown in this scheme will be neutral or positive depending on the identity of X.

Fig. 11. Depiction of isomerisation pathways in SABRE complexes via the five coordinate intermediate [Ir(H)₂(IMes)(Sub)₂]⁺.

Fig. 12. (a) Example iridium phosphine complexes used for catalytic polarisation transfer from para-H₂. Reported examples are based on traditional monodentate κ¹-P phosphine ligands (left), κ³-N,P,P pincer ligands (middle) or κ²-N,P phox ligands (right). (b) SABRE catalysts containing different auxiliary NHC ligands. (c) Effect of para substituted NHC ligands as a function of their TEP on the rate of substrate dissociation from [Ir(H)₂(NHC)(sub)₃]Cl at 298 K where substrate is methyl-4,6-d₂-nicotinate. The outlier, 35 (shown in red), is attributed to steric effects of the bulky ^tBu group. Adapted from ref. .

Fig. 13. Reported examples of water-soluble SABRE catalysts.

Fig. 14. (a) Formation of sulfoxide-containing SABRE catalysts that can hyperpolarise O-donor ketoacids. (b) Example use of these catalysts to achieve hyperpolarisation of pyruvate. Partial hyperpolarised ¹³C NMR spectra for the keto region (left) and carbonyl region (right) recorded after [IrCl(COD)(IMes)] (5 mM), methylphenylsulfoxide (50 mM), and sodium pyruvate-1,2-[¹³C₂] (30 mM) are shaken in methanol-d₄ (0.6 mL) with 3 bar para-H₂ for 30 seconds in a mu-metal shield. (c) Example use of these catalysts to achieve hyperpolarisation of ketoisocaproate. Partial hyperpolarised ¹³C NMR spectra when [IrCl(COD)(IMes)] (5 mM) and ketoisocaproate-1-[¹³C] are shaken with dimethylsulfoxide (50 mM) and para-H₂ (3 bar) in methanol-d₄ (0.6 mL) for 10 seconds in a mu-metal shield at ca. 1 μT. The signals marked by a red asterisk denote singlet magnetisation of naturally abundant ketoisocaproate-1,2-[¹³C₂]. Adapted from (b) ref. and (c) ref. .

Fig. 15. Example X-ray crystal structures of catalyst decomposition products reported in ref. (upper left), ref. (upper right) and ref. (lower). Note that thermal ellipsoids are shown at 50% probability and all non-hydride hydrogen atoms and solvent of crystallisation have been omitted for clarity.

Fig. 16. Cobalt-based system used to achieve both PHIP and SABRE-like hyperpolarisation. (a) Simplified mechanism showing ways in which alkenes can become hydrogenated using para-H₂ to give PHIP for alkane products, or the starting alkene can become hyperpolarised in a SABRE or PHIP-IE pathway. (b) Example ¹H OPSY spectrum showing enhanced ¹H NMR signals due to both PHIP and SABRE/PHIP-IE for phenylethane and phenylpropene respectively. (c) ¹⁹F NMR Spectrum for fluorophenylpropene and fluorophenylpropane hyperpolarised using these cobalt systems. Adapted from (b) ref. and (c) ref. .

Fig. 17. (a) Reaction scheme showing the formation of PHIP-hyperpolarised [1-¹³C]-fumarate from trans hydrogenation of an unsaturated [1-¹³C]acetylene dicarboxylate precursor. Proton magnetisation is transferred to the ¹³C site by magnetic field cycling (MFC). Metabolic conversion following in vivo injection can give rise to [1-¹³C]-malate and [4-¹³C]-malate products. Note that * represents a ¹³C labelled site and the nuclei represented in black circles are hyperpolarised. (b) Time course of hyperpolarised fumarate and malate in a suspension of lysed EL-4 tumour at 14.1 T with an example single acquisition (inset). Adapted from ref. . (c) In vivo¹³C chemical shift imaging of PHIP-hyperpolarised [1-¹³C]-fumarate and its metabolic products in an acetaminophen-induced hepatitis mouse at 1.5 T. An example single voxel ¹³C NMR spectrum is shown in the upper left. Maps of hyperpolarised ¹³C signal intensity for [1-¹³C]-fumarate (upper right) and both [1-¹³C] and [4-¹³C]malate (lower left) are shown with a parametric map of the malate/fumarate ratio (lower right). Adapted from ref. .

Fig. 18. (a) The enhanced hydride NMR signals of PHIP and SABRE catalysts can provide significant chemical shift resolution which is of great use for the indirect detection of analytes in mixtures. (b) Example 2D NMR measurements that utilise PHIP hyperpolarisation of metal dihydride catalysts for sensing and identification of complex mixtures of amino acids. Adapted from ref. .

Ben. J. Tickner

Vladimir V. Zhivonitko