Metal-Mediated Catalytic Polarization Transfer from para Hydrogen to 3,5-Dihalogenated Pyridines.

The neutral catalysts [IrCl(H)2(NHC)(substrate)2] or [IrCl(H)2(NHC)(substrate)(sulfoxide)] are used to transfer polarization from para hydrogen (pH2) to 3,5-dichloropyridine and 3,5-dibromopyridine substrates. This is achieved in a rapid, reversible, and low-cost process that relies on ligand exchange within the active catalyst. Notably, the sulfoxide-containing catalyst systems produced NMR signal enhancements between 1 and 2 orders of magnitude larger than its unmodified counterpart. Consequently, this signal amplification by reversible exchange hyperpolarization method can boost the 1H, 13C, and 15N nuclear magnetic resonance (NMR) signal intensities by factors up to 4350, 1550, and 46,600, respectively (14.0, 1.3, and 15.4% polarization). In this paper, NMR and X-ray crystallography are used to map the evolution of catalytically important species and provide mechanistic rational for catalytic efficiency. Furthermore, applications in spontaneous radiofrequency amplification by stimulated emission and NMR reaction monitoring are also shown.

Enhancing the NMR signals of plant oil components using hyperpolarisation relayed via proton exchange.

In this work, the limited sensitivity of magnetic resonance is addressed by using the hyperpolarisation method relayed signal amplification by reversible exchange (SABRE-Relay) to transfer latent magnetism from para-hydrogen, a readily isolated spin isomer of hydrogen gas, to components of key plant oils such as citronellol, geraniol, and nerol. This is achieved via relayed polarisation transfer in which an [Ir(H)2(IMes)(NH2R)3]Cl type complex produces hyperpolarised NH2R free in solution, before labile proton exchange between the hyperpolarisation carrier (NH2R) and the OH-containing plant oil component generates enhanced NMR signals for the latter. Consequently, up to ca. 200-fold 1H (0.65% 1H polarisation) and 800-fold 13C NMR signal enhancements (0.65% 13C polarisation) are recorded for these essential oils in seconds. Remarkably, the resulting NMR signals are not only diagnostic, but prove to propagate over large spin systems via a suitable coupling network. A route to optimise the enhancement process by varying the identity of the carrier NH2R, and its concentration is demonstrated. In order to prove utility, these pilot measurements are extended to study a much wider range of plant-derived molecules including rhodinol, verbenol, (1R)-endo-(+)-fenchyl alcohol, (-)-carveol, and linalool. Further measurements are then described which demonstrate citronellol and geraniol can be detected in an off-the-shelf healthcare product rose geranium oil at concentrations of just a few tens of µM in single scan 1H NMR measurements, which are not visible in comparable thermally polarised NMR experiments. This work therefore presents a significant expansion of the types of molecules amenable to hyperpolarisation using para-hydrogen and illustrates a real-world application in the diagnostic detection of low concentration analytes in mixtures.

Opportunities and challenges with hyperpolarized bioresponsive probes for functional imaging using magnetic resonance.

The development of hyperpolarized bioresponsive probes for magnetic resonance imaging (MRI) applications is an emerging and rapidly growing topic in chemistry. A wide range of hyperpolarized molecular biosensors for functional MRI have been developed in recent years. These probes comprise many different types of small-molecule reporters that can be hyperpolarized using dissolution dynamic nuclear polarization and parahydrogen-induced polarization or xenon-chelated macromolecular conjugates hyperpolarized using spin-exchange optical pumping. In this Perspective, we discuss how the amplified magnetic resonance signals of these agents are responsive to biologically relevant stimuli such as target proteins, reactive oxygen species, pH or metal ions. We examine how functional MRI using these systems allows a great number of biological processes to be monitored rapidly. Consequently, hyperpolarized bioresponsive probes may play a critical role in functional molecular imaging for observing physiology and pathology in real time.

Toward Optimizing and Understanding Reversible Hyperpolarization of Lactate Esters Relayed from para-Hydrogen.

The SABRE-Relay hyperpolarization method is used to enhance the 1H and 13C NMR signals of lactate esters, which find use in a wide range of medical, pharmaceutical, and food science applications. This is achieved by the indirect relay of magnetization from para-hydrogen, a spin isomer of dihydrogen, to OH-containing lactate esters via a SABRE-hyperpolarized NH intermediary. This delivers 1H and 13C NMR signal enhancements as high as 245- and 985-fold, respectively, which makes the lactate esters far more detectable using NMR. DFT-calculated J-couplings and spin dynamics simulations indicate that, while polarization can be transferred from the lactate OH to other 1H nuclei via the J-coupling network, incoherent mechanisms are needed to polarize the 13C nuclei at the 6.5 mT transfer field used. The resulting sensitivity boost is predicted to be of great benefit for the NMR detection and quantification of low concentrations (

In Situ Ternary Adduct Formation of Yttrium Polyaminocarboxylates Leads to Small Molecule Capture and Activation.

In this work the chemistry of yttrium complexes is exploited for small molecule capture and activation. Nuclear magnetic resonance (NMR) and density functional theory (DFT) studies were used to investigate the in situ formation of solution state ternary yttrium-acetate, yttrium-bicarbonate, and yttrium-pyruvate adducts with a range of polyaminocarboxylate chelates. These studies reveal that [Y(DO3A)(H2 O)2 ] (H3 DO3A - 1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylic acid) and [Y(EDTA)(H2 O)q ]- (H4 EDTA - ethylenediaminetetraacetic acid, q = 2 and 3) are able to form ternary adducts with bicarbonate and pyruvate. In the latter, unusual decarboxylation of pyruvate to form acetic acid and CO2 was observed and further studied using SABRE-hyperpolarised 13 C NMR (SABRE - signal amplification by reversible exchange) to provide information about the reaction timescale and lifetime of intermediates involved in this conversion. The work presented demonstrates that yttrium complexes can capture and activate small molecules, which may lead to novel and useful applications of this metal in catalysis and medical imaging.

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

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.

Hyperpolarised NMR to aid molecular profiling of electronic cigarette aerosols.

Signal amplification by reversible exchange (SABRE) hyperpolarisation is used to enhance the NMR signals of nicotine and acrolein in methanol-d4 solutions of electronic cigarette aerosols. Consequently, detection of 74 µM nicotine is possible in just a single scan 1H NMR spectrum. The first example of an aldehyde hyperpolarised using SABRE is demonstrated and we work towards novel real-world applications of SABRE-hyperpolarised NMR for chemical analysis.

Ultrafast Laplace NMR to study metal-ligand interactions in reversible polarisation transfer from parahydrogen.

Laplace Nuclear Magnetic Resonance (NMR) can determine relaxation parameters and diffusion constants, giving valuable information about molecular structure and dynamics. Information about relaxation times (T1 and T2) and the self-diffusion coefficient (D) can be extracted from exponentially decaying NMR signals by performing a Laplace transform, which is a different approach to traditional NMR involving Fourier transform of a free induction decay. Ultrafast Laplace NMR uses spatial encoding to collect the entire data set in just a single scan which provides orders of magnitude time savings. In this work we use ultrafast Laplace NMR D-T2 correlation sequences to measure key relaxation (T2) and diffusion (D) parameters of methanolic solutions containing pyridine. For the first time we combine this technique with the hyperpolarisation technique Signal Amplification By Reversible Exchange (SABRE), which employs an iridium catalyst to reversibly transfer polarisation from parahydrogen, to boost the 1H NMR signals of pyridine by up to 300-fold. We demonstrate use of ultrafast Laplace NMR to monitor changes in pyridine T2 and D associated with ligation to the iridium SABRE catalyst and kinetic isotope exchange reactions. The combined 1440-fold reduction in experiment time and 300-fold 1H NMR signal enhancement allow the determination of pyridine D coefficients and T2 values at 25 mM concentrations in just 3 seconds using SABRE hyperpolarised ultrafast Laplace NMR.

Exploring the hyperpolarisation of EGTA-based ligands using SABRE.

The design of molecules whose magnetic resonance (MR) signals report on their biological environment is receiving attention as a route to non-invasive functional MR. Hyperpolarisation techniques improve the sensitivity of MR and enable real time low concentration MR imaging, allowing for the development of novel functional imaging methodologies. In this work, we report on the synthesis of a series of EGTA-derived molecules (EGTA - ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid), whose core structures are known to bind biologically relevant metal ions in vivo, in addition to pyridyl rings that allow reversible ligation to an iridium dihydride complex. Consequently, they are amenable to hyperpolarisation through the parahydrogen-based signal amplification by reversible exchange (SABRE) process. We investigate how the proximity of EGTA and pyridine units, and the identity of the linker group, affect the SABRE hyperpolarisation attained for each agent. We also describe the effect of catalyst identity and co-ligand presence on these measurements and can achieve 1H NMR signal enhancements of up to 160-fold. We rationalise these results to suggest the design elements needed for probes amenable to SABRE hyperpolarisation whose MR signals might in the future report on the presence of metal ions.

Reversible Hyperpolarization of Ketoisocaproate Using Sulfoxide-containing Polarization Transfer Catalysts.

The substrate scope of sulfoxide-containing magnetisation transfer catalysts is extended to hyperpolarize α-ketoisocaproate and α-ketoisocaproate-1-[13 C]. This is achieved by forming [Ir(H)2 (κ2 -ketoisocaproate)(N-heterocyclic carbene)(sulfoxide)] which transfers latent magnetism from p-H2 via the signal amplification by reversible exchange (SABRE) process. The effect of polarization transfer field on the formation of enhanced 13 C magnetization is evaluated. Consequently, performing SABRE in a 0.5 µT field enabled most efficient magnetisation transfer. 13 C NMR signals for α-ketoisocaproate-1-[13 C] in methanol-d4 are up to 985-fold more intense than their traditional Boltzmann derived signal intensity (0.8 % 13 C polarisation). Single crystal X-ray diffraction reveals the formation of the novel catalyst decomposition products [Ir(µ-H)(H)2 (IMes)(SO(Ph)(Me)2 )]2 and [(Ir(H)2 (IMes)(SO(Me)2 ))2 (µ-S)] when the sulfoxides methylphenylsulfoxide and dimethylsulfoxide are used respectively.

The use of yttrium in medical imaging and therapy: historical background and future perspectives.

Yttrium is a chemically versatile rare earth element that finds use in a range of applications including lasers and superconductors. In medicine, yttrium-based materials are used in medical lasers and biomedical implants. This is extended through the array of available yttrium isotopes to enable roles for 90Y complexes as radiopharmaceuticals and 86Y tracers for positron emission tomography (PET) imaging. The naturally abundant isotope 89Y is proving to be suitable for nuclear magnetic resonance investigations, where initial reports in the emerging field of hyperpolarised magnetic resonance imaging (MRI) are promising. In this review we explore the coordination and radiochemical properties of yttrium, and its role in drugs for radiotherapy, PET imaging agents and perspectives for applications in hyperpolarised MRI.

Optimisation of pyruvate hyperpolarisation using SABRE by tuning the active magnetisation transfer catalyst.

Hyperpolarisation techniques such as signal amplification by reversible exchange (SABRE) can deliver NMR signals several orders of magnitude larger than those derived under Boltzmann conditions. SABRE is able to catalytically transfer latent magnetisation from para-hydrogen to a substrate in reversible exchange via temporary associations with an iridium complex. SABRE has recently been applied to the hyperpolarisation of pyruvate, a substrate often used in many in vivo MRI studies. In this work, we seek to optimise the pyruvate-13C2 signal gains delivered through SABRE by fine tuning the properties of the active polarisation transfer catalyst. We present a detailed study of the effects of varying the carbene and sulfoxide ligands on the formation and behaviour of the active [Ir(H)2(η2-pyruvate)(sulfoxide)(NHC)] catalyst to produce a rationale for achieving high pyruvate signal gains in a cheap and refreshable manner. This optimisation approach allows us to achieve signal enhancements of 2140 and 2125-fold for the 1-13C and 2-13C sites respectively of sodium pyruvate-1,2-[13C2].

Using SABRE Hyperpolarized 13C NMR Spectroscopy to Interrogate Organic Transformations of Pyruvate.

Signal amplification by reversible exchange (SABRE) is a hyperpolarization technique that uses a metal complex to catalytically transfer magnetization from parahydrogen to molecules of interest. SABRE is used here to monitor the decarboxylation of sodium pyruvate-1,2-[13C2] at a 15 mM concentration to form ethanoic acid and CO2 upon reaction with hydrogen peroxide (150 mM). The rate constant of this reaction is determined by hyperpolarized 13C SABRE-NMR spectroscopy as 0.056 ± 0.003 dm3 mol-1 s-1 at 298 K and is comparable to that determined from thermal 1H NMR (k = 0.050 ± 0.003 dm3 mol-1 s-1) and UV measurements (k = 0.053 ± 0.001 dm3 mol-1 s-1). The hyperpolarized reaction intermediate 2-hydroperoxy-2-hydroxypropanoate is detected in a single scan hyperpolarized 13C NMR spectrum. This work highlights how SABRE hyperpolarization can be used as a tool for the precise monitoring of chemical transformations by hyperpolarized NMR spectroscopy.

Probing the Hydrogenation of Vinyl Sulfoxides Using para-Hydrogen.

Vinyl sulfoxides are an important functional group used in a wide range of organic transformations. Here, we use [IrCl(COD)(IMes)] where IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene and COD = cis,cis-1,5-cyclooctadiene to rapidly hydrogenate phenylvinylsulfoxide. We use para-hydrogen-induced hyperpolarization (PHIP) to follow this reaction with [IrCl(H)2(IMes)(S(O)(Ph)(Et))2] dominating in the later stages. Decomposition to form the reduced C-S bond cleavage product [Ir2(H)3(κ2-H)(κ2-SPh)2(IMes)2(S(Et)(Ph)O)] limits turnover. The related product [Ir2(H)4(κ2-S)(IMes)2(S(O)(CH2Ph)2)2] is formed from dibenzylsulfoxide, demonstrating the wider utility of this transformation.

Relayed hyperpolarization from para-hydrogen improves the NMR detectability of alcohols.

The detection of alcohols by magnetic resonance techniques is important for their characterization and the monitoring of chemical change. Hyperpolarization processes can make previously inpractical measurements, such as the determination of low concentration intermediates, possible. Here, we investigate the SABRE-Relay method in order to define its key characteristics and improve the resulting 1H NMR signal gains which subsequently approach 103 per proton. We identify optimal amine proton transfer agents for SABRE-Relay and show how catalyst structure influences the outcome. The breadth of the method is revealed by expansion to more complex alcohols and the polarization of heteronuclei.

Mechanistic insight into novel sulfoxide containing SABRE polarisation transfer catalysts.

Signal Amplification By Reversible Exchange (SABRE) is a hyperpolarisation technique that commonly uses [Ir(H)2(carbene)(substrate)3]Cl complexes to catalytically transfer magnetisation from para-hydrogen derived hydride ligands to coordinated substrates. Here, we explore the reactivity of a novel class of such catalysts based on sulfoxide containing [IrCl(H)2(carbene)(DMSO)2], which are involved in the hyperpolarisation of pyruvate using SABRE. We probe the reactivity of this species by NMR and DFT and upon reaction with sodium pyruvate establish the formation of two isomers of [Ir(H)2(η2-pyruvate)(DMSO)(IMes)]. Studies with related disodium oxalate yield [Ir2(H)4(IMes)2(DMSO)2(η2-κ2-Oxalate)] that is characterised by NMR and X-ray diffraction.

Using coligands to gain mechanistic insight into iridium complexes hyperpolarized with para-hydrogen.

We report the formation of a series of novel [Ir(H)2(IMes)(α-13C2-carboxyimine)L] complexes in which the identity of the coligand L is varied. When examined with para-hydrogen, complexes in which L is benzylamine or phenethylamine show significant 1H hydride and 13C2 imine enhancements and may exist in 13C2 singlet spin order. Isotopic labeling techniques are used to double 13C2 enhancements (up to 750-fold) and singlet state lifetimes (up to 20 seconds) compared to those previously reported. Exchange spectroscopy and Density Functional Theory are used to investigate the stability and mechanism of rapid hydrogen exchange in these complexes, a process driven by dissociative coligand loss to form a key five coordinate intermediate. When L is pyridine or imidazole, competitive binding to such intermediates leads to novel complexes whose formation, kinetics, behaviour, structure, and hyperpolarization is investigated. The ratio of the observed PHIP enhancements were found to be affected not only by the hydrogen exchange rates but the identity of the coligands. This ligand reactivity is accompanied by decoherence of any 13C2 singlet order which can be preserved by isotopic labeling. Addition of a thiol coligand proved to yield a thiol oxidative addition product which is characterized by NMR and MS techniques. Significant 870-fold 13C enhancements of pyridine can be achieved using the Signal Amplification By Reversible Exchange (SABRE) process when α-carboxyimines are used to block active coordination sites. [Ir(H)2(IMes)(α-13C2-carboxyimine)L] therefore acts as unique sensors whose 1H hydride chemical shifts and corresponding hyperpolarization levels are indicative of the identity of a coligand and its binding strength.

Hyperpolarising Pyruvate through Signal Amplification by Reversible Exchange (SABRE).

Hyperpolarisation methods that premagnetise agents such as pyruvate are currently receiving significant attention because they produce sensitivity gains that allow disease tracking and interrogation of cellular metabolism by magnetic resonance. Here, we communicate how signal amplification by reversible exchange (SABRE) can provide strong 13 C pyruvate signal enhancements in seconds through the formation of the novel polarisation transfer catalyst [Ir(H)2 (η2 -pyruvate)(DMSO)(IMes)]. By harnessing SABRE, strong signals for [1-13 C]- and [2-13 C]pyruvate in addition to a long-lived singlet state in the [1,2-13 C2 ] form are readily created; the latter can be observed five minutes after the initial hyperpolarisation step. We also demonstrate how this development may help with future studies of chemical reactivity.

Iridium α-Carboxyimine Complexes Hyperpolarized with para-Hydrogen Exist in Nuclear Singlet States before Conversion into Iridium Carbonates.

The formation and hyperpolarization of an [Ir(H)2 (amine)(IMes)(η2 -imine)]Cl complex that can be created in a hyperpolarized nuclear singlet state is reported. These complexes are formed when an equilibrium mixture of pyruvate, amine (benzylamine or phenylethylamine), and the corresponding imine condensation product, react with preformed [Ir(H)2 (amine)3 (IMes)]Cl. These iridium α-carboxyimine complexes exist as two regioisomers differentiated by the position of amine. When examined with para-hydrogen the hydride resonances of the isomer with amine trans to hydride become strongly hyperpolarized. The initial hydride singlet states readily transfer to the corresponding 13 C2 state in the labelled imine and exhibit magnetic state lifetimes of up to 11 seconds. Their 13 C signals have been detected with up to 420 fold signal gains at 9.4 T. On a longer timescale, and in the absence of H2 , further reaction leads to the formation of neutral carbonate containing [Ir(amine)(η2 -CO3 )(IMes)(η2 -imine)]. Complexes are characterized by, IR, MS, NMR and X-ray diffraction.