Coherent Evolution of Signal Amplification by Reversible Exchange in Two Alternating Fields (alt-SABRE)

Parahydrogen (pH₂) is a convenient and cost-efficient source of spin order to enhance the magnetic resonance signal. Previous work showed that transient interaction of pH₂ with a metal organic complex in a signal amplification by reversible exchange (SABRE) experiment enabled more than 10 % polarization for some ¹⁵N molecules. Here, we analyzed a variant of SABRE, consisting of a magnetic field alternating between a low field of ∼1 μT, where polarization transfer is expected to take place, and a higher field >50 μT (alt-SABRE). These magnetic fields affected the amplitude and frequency of polarization transfer. Deviation of a lower magnetic field from a “perfect” condition of level anti-crossing increases the frequency of polarization transfer that can be exploited for polarization of short-lived transient SABRE complexes. Moreover, the coherences responsible for polarization transfer at a lower field persisted during magnetic field variation and continued their spin evolution at higher field with a frequency of 2.5 kHz at 54 μT. The latter should be taken into consideration for an efficient alt-SABRE. Theoretical and experimental findings were exemplified with Iridium N-heterocyclic carbene SABRE complex and ¹⁵N-acetonitrole, where a 30 % higher ¹⁵N polarization with alt-SABRE compared to common SABRE was reached.     

Synthesis and 15N NMR Signal Amplification by Reversible Exchange of [15N]Dalfampridine at Microtesla Magnetic Fields

Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare ¹⁵N-labeled [¹⁵N]dalfampridine (4-amino[¹⁵N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE-SHEATH technique) with up to 2.0 % ¹⁵N polarization. The 7-hour-long activation of SABRE pre-catalyst [Ir(IMes)(COD)Cl] in the presence of [¹⁵N]dalfampridine can be remedied by the use of pyridine co-ligand for catalyst activation while retaining the ¹⁵N polarization levels of [¹⁵N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on ¹⁵N polarization levels of free and equatorial catalyst-bound [¹⁵N]dalfampridine were investigated. Moreover, we studied ¹⁵N polarization build-up and decay at magnetic field of less than 0.04 μT as well as ¹⁵N polarization decay at the Earth's magnetic field and at 1.4 T.     

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 ¹³C 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 [1‐¹³C]‐ and [2‐¹³C]pyruvate in addition to a long‐lived singlet state in the [1,2‐¹³C₂] 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.     

Signal Amplification by Reversible Exchange (SABRE): From Discovery to Diagnosis

Signal amplification by reversible exchange (SABRE) turns typically weak magnetic resonance responses into strong signals making previously impractical measurements possible. This technique has gained significant popularity because of its speed and simplicity. This Minireview tracks the development of SABRE from the initial hyperpolarization of pyridine in 2009 to the point in which 50 % ¹H polarization levels have been achieved in a di‐deuterio‐nicotinate, a key step in the pathway to potential clinical use. Simple routes to highly efficient ¹⁵N hyperpolarization and the creation of hyperpolarized long‐lived magnetic states are illustrated. To conclude, we describe how the recently reported SABRE‐RELAY approach offers a route for parahydrogen to hyperpolarize a much wider array of molecular scaffolds, such as amides, alcohols, carboxylic acids, and phosphates, than was previously thought possible. We predict that collectively these developments ensure that SABRE will significantly impact on both chemical analysis and the diagnosis of disease in the future.     

Density Functional Theory Study of Reaction Equilibria in Signal Amplification by Reversible Exchange

An in-depth theoretical analysis of key chemical equilibria in Signal Amplification by Reversible Exchange (SABRE) is provided, employing density functional theory calculations to characterize the likely reaction network. For all reactions in the network, the potential energy surface is probed to identify minimum energy pathways. Energy barriers and transition states are calculated, and harmonic transition state theory is applied to calculate exchange rates that approximate experimental values. The reaction network energy surface can be modulated by chemical potentials that account for the dependence on concentration, temperature, and partial pressure of molecular constituents (hydrogen, methanol, pyridine) supplied to the experiment under equilibrium conditions. We show that, under typical experimental conditions, the Gibbs free energies of the two key states involved in pyridine-hydrogen exchange at the common Ir-IMes catalyst system in methanol are essentially the same, i. e., nearly optimal for SABRE. We also show that a methanol-containing intermediate is plausible as a transient species in the process.     

“Direct” 13C Hyperpolarization of 13C‐Acetate by MicroTesla NMR Signal Amplification by Reversible Exchange (SABRE)

Herein, we demonstrate “direct” ¹³C hyperpolarization of ¹³C‐acetate via signal amplification by reversible exchange (SABRE). The standard SABRE homogeneous catalyst [Ir‐IMes; [IrCl(COD)(IMes)], (IMes=1,3‐bis(2,4,6‐trimethylphenyl), imidazole‐2‐ylidene; COD=cyclooctadiene)] was first activated in the presence of an auxiliary substrate (pyridine) in alcohol. Following addition of sodium 1‐¹³C‐acetate, parahydrogen bubbling within a microtesla magnetic field (i.e. under conditions of SABRE in shield enables alignment transfer to heteronuclei, SABRE‐SHEATH) resulted in positive enhancements of up to ≈100‐fold in the ¹³C NMR signal compared to thermal equilibrium at 9.4 T. The present results are consistent with a mechanism of “direct” transfer of spin order from parahydrogen to ¹³C spins of acetate weakly bound to the catalyst, under conditions of fast exchange with respect to the ¹³C acetate resonance, but we find that relaxation dynamics at microtesla fields alter the optimal matching from the traditional SABRE‐SHEATH picture. Further development of this approach could lead to new ways to rapidly, cheaply, and simply hyperpolarize a broad range of substrates (e.g. metabolites with carboxyl groups) for various applications, including biomedical NMR and MRI of cellular and in vivo metabolism.     

Synthetic Approaches for 15N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for 15N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high-resolution NMR spectroscopy to real-time metabolic imaging in vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the ¹³C and ¹⁵N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T₁ allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low-cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of ¹⁵N nuclei. Although large sensitivity gains are enabled by hyperpolarization, ¹⁵N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of ¹⁵N-labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques.     

Coumaraz‐2‐on‐4‐ylidene: Ambiphilic N‐Heterocyclic Carbenes with a Tunable Electronic Structure

Herein, a coumaraz‐2‐on‐4‐ylidene ( 1 ) as a new example of an ambiphilic N‐heterocyclic carbene, having electronic properties that can be fine‐tuned, is reported. The N‐carbamic and aryl groups on the carbene carbon center provide exceptionally high electrophilicity and nucleophilicity simultaneously to the carbene center, as evidenced by the ⁷⁷Se NMR chemical shifts of their selenoketone derivatives and the CO stretching strengths of their rhodium carbonyl complexes. Since the precursors of 1 could be synthesized from various functionalized Schiff bases in a practical and scalable manner, the electronic properties of 1 can be fine‐tuned in a quantitative and predictable way by using the Hammett σ constant of the functional groups on aryl ring. The facile electronic tuning capability of 1 may be applicable to eliciting novel properties in main‐group and transition‐metal chemistry.     

Studies on Electronic Effects in O‐, N‐ and S‐Chelated Ruthenium Olefin‐Metathesis Catalysts

A short overview on the structural design of the Hoveyda–Grubbs‐type ruthenium initiators chelated through oxygen, nitrogen or sulfur atoms is presented. Our aim was to compare and contrast O‐, N‐ and S‐chelated ruthenium complexes to better understand the impact of electron‐withdrawing and ‐donating substituents on the geometry and activity of the ruthenium complexes and to gain further insight into the trans–cis isomerisation process of the S‐chelated complexes. To evaluate the different effects of chelating heteroatoms and to probe electronic effects on sulfur‐ and nitrogen‐chelated latent catalysts, we synthesised a series of novel complexes. These catalysts were compared against two well‐known oxygen‐chelated initiators and a sulfoxide‐chelated complex. The structures of the new complexes have been determined by single‐crystal X‐ray diffraction and analysed to search for correlations between the structural features and activity. The replacement of the oxygen‐chelating atom by a sulfur or nitrogen atom resulted in catalysts that were inert at room temperature for typical ring‐closing metathesis (RCM) and cross‐metathesis reactions and showed catalytic activity only at higher temperatures. Furthermore, one nitrogen‐chelated initiator demonstrated thermo‐switchable behaviour in RCM reactions, similar to its sulfur‐chelated counterparts.     

A Facile Route to Backbone‐Tethered N‐Heterocyclic Carbene (NHC) Ligands via NHC to aNHC Rearrangement in NHC Silicon Halide Adducts

The reaction of 1,3‐diisopropylimidazolin‐2‐ylidene (iPr₂Im) with diphenyldichlorosilane (Ph₂SiCl₂) leads to the adduct (iPr₂Im)SiCl₂Ph₂ 1 . Prolonged heating of isolated 1 at 66 °C in THF affords the backbone‐tethered bis(imidazolium) salt [(^aHiPr₂Im)₂SiPh₂]²⁺ 2 Cl^? 2 (“^a” denotes “abnormal” coordination of the NHC), which can be synthesized in high yields in one step starting from two equivalents of iPr₂Im and Ph₂SiCl₂. Imidazolium salt 2 can be deprotonated in THF at room temperature using sodium hydride as a base and catalytic amounts of sodium tert‐butoxide to give the stable N‐heterocyclic dicarbene (^aiPr₂Im)₂SiPh₂ 3 , in which two NHCs are backbone‐tethered with a SiPh₂ group. This easy‐to‐synthesize dicarbene 3 can be used as a novel ligand type in transition metal chemistry for the preparation of dinuclear NHC complexes, as exemplified by the synthesis of the homodinuclear copper(I) complex [{^a(ClCu?iPr₂Im)}₂SiPh₂] 4 .     

Recent Advances in the Chemistry of N‐Heterocyclic‐Carbene‐Functionalized Metal‐Nanoparticles and Their Applications

Metal‐nanoparticles (M‐NPs) have been widely applied in catalysis, imaging, sensing and medicine. One particularly active area of this research is the modification of the surface of the nanoparticles to prevent aggregation through the coordination of ligands. N‐Heterocyclic carbenes (NHCs) have emerged as suitable ligands for this purpose due to their affinity to the metals and their strongly electron donating nature. A number of rationally designed NHC‐modified M‐NPs have been developed using strategies based on metal complex decomposition and ligand exchange. Herein, NHC‐stabilized M‐NPs based on a range of transition metals, especially the recent advances, were summarized.     

Copper‐Catalyzed Enantioselective Markovnikov Protoboration of α‐Olefins Enabled by a Buttressed N‐Heterocyclic Carbene Ligand

Reported is a highly enantioselective copper‐catalyzed Markovnikov protoboration of unactivated terminal alkenes. A variety of simple and abundant feedstock α‐olefins bearing a diverse array of functional groups and heterocyclic substituents can be used as substrates, and the reaction proceeds under mild reaction conditions at ambient temperature to provide expedient access to enantioenriched alkylboronic esters in good regioselectivity and with excellent enantiocontrol. Critical to the success of the protocol was the development and application of a novel, sterically hindered N‐heterocyclic carbene, (R,R,R,R)‐ANIPE, as the ligand for copper.     

Cationic Bis‐N‐Heterocyclic Carbene (NHC) Ruthenium Complex: Structure and Application as Latent Catalyst in Olefin Metathesis

An unexpected cationic bis‐N‐heterocyclic carbene (NHC) benzylidene ether based ruthenium complex ( 2 a ) was prepared through the double incorporation of an unsymmetrical unsaturated N‐heterocyclic carbene (U₂‐NHC) ligand that bore an N‐substituted cyclododecyl side chain. The isolation and full characterization (including X‐ray diffraction studies) of key synthetic intermediates along with theoretical calculations allowed us to understand the mechanism of the overall cationization process. Finally, the newly developed complex 2 a displayed interesting latent behavior during ring‐closing metathesis, which could be “switched on” under acidic conditions.     

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 ¹H magnetic resonance imaging (MRI) of 1 % hyperpolarized flowing gas with microscale spatial resolution (625×625×625 μm³) and large imaging matrix (128×128×32) was demonstrated by using a preclinical 4.7 T scanner and 17.4 s imaging scan time.     

Selective hydrosilylation of ketones catalyzed by in situ‐generated iron NHC complexes

Aryl alkyl‐, heteroaryl alkyl‐ and dialkyl ketones were readily reduced to their corresponding secondary alcohols in high yields, using the commercially available and inexpensive polymeric silane polymethylhydrosiloxane (PMHS), as reducing agent. The reaction is catalyzed by an in situ ‐generated iron complex, conveniently generated from iron(II) acetate and the commercially available N‐heterocyclic carbene (NHC) precursor IPr·HCl. Copyright © 2011 John Wiley & Sons, Ltd.     

Extending the Substrate Scope of Bicyclic P‐Oxazoline/Thiazole Ligands for Ir‐Catalyzed Hydrogenation of Unfunctionalized Olefins by Introducing a Biaryl Phosphoroamidite Group

This study identifies a series of Ir‐bicyclic phosphoroamidite–oxazoline/thiazole catalytic systems that can hydrogenate a wide range of minimally functionalized olefins (including E‐ and Z‐tri‐ and disubstituted substrates, vinylsilanes, enol phosphinates, tri‐ and disubstituted alkenylboronic esters, and α,β‐unsaturated enones) in high enantioselectivities (ee values up to 99 %) and conversions. The design of the new phosphoroamidite–oxazoline/thiazole ligands derives from a previous successful generation of bicyclic N‐phosphane–oxazoline/thiazole ligands, by replacing the N‐phosphane group with a π‐acceptor biaryl phosphoroamidite moiety. A small but structurally important family of Ir‐phosphoroamidite–oxazoline/thiazole precatalysts has thus been synthesized by changing the nature of the N‐donor group (either oxazoline or thiazole) and the configuration at the biaryl phosphoroamidite moiety. The substitution of the N‐phosphane by a phosphoroamidite group in the bicyclic N‐phosphane–oxazoline/thiazole ligands extended the range of olefins that can be successfully hydrogenated.     

The Influence of N‐Heterocyclic Carbenes (NHC) on the Reactivity of [Ru(NHC)4H]+ With H2, N2, CO and O2

The five‐coordinate ruthenium N‐heterocyclic carbene (NHC) hydrido complexes [Ru(IiPr₂Me₂)₄H][BAr^F₄] ( 1 ; IiPr₂Me₂=1,3‐diisopropyl‐4,5‐dimethylimidazol‐2‐ylidene; Ar^F=3,5‐(CF₃)₂C₆H₃), [Ru(IEt₂Me₂)₄H][BAr^F₄] ( 2 ; IEt₂Me₂=1,3‐diethyl‐4,5‐dimethylimidazol‐2‐ylidene) and [Ru(IMe₄)₄H][BAr^F₄] ( 3 ; IMe₄=1,3,4,5‐tetramethylimidazol‐2‐ylidene) have been synthesised following reaction of [Ru(PPh₃)₃HCl] with 4–8 equivalents of the free carbenes at ambient temperature. Complexes 1 – 3 have been structurally characterised and show square pyramidal geometries with apical hydride ligands. In both dichloromethane or pyridine solution, 1 and 2 display very low frequency hydride signals at about δ ?41. The tetramethyl carbene complex 3 exhibits a similar chemical shift in toluene, but shows a higher frequency signal in acetonitrile arising from the solvent adduct [Ru(IMe₄)₄(MeCN)H][BAr^F₄], 4 . The reactivity of 1 – 3 towards H₂ and N₂ depends on the size of the N‐substituent of the NHC ligand. Thus, 1 is unreactive towards both gases, 2 reacts with both H₂ and N₂ only at low temperature and incompletely, while 3 affords [Ru(IMe₄)₄(η²‐H₂)H][BAr^F₄] ( 7 ) and [Ru(IMe₄)₄(N₂)H][BAr^F₄] ( 8 ) in quantitative yield at room temperature. CO shows no selectivity, reacting with 1 – 3 to give [Ru(NHC)₄(CO)H][BAr^F₄] ( 9 – 11 ). Addition of O₂ to solutions of 2 and 3 leads to rapid oxidation, from which the Ru^III species [Ru(NHC)₄(OH)₂][BAr^F₄] and the Ru^IV oxo chlorido complex [Ru(IEt₂Me₂)₄(O)Cl][BAr^F₄] were isolated. DFT calculations reproduce the greater ability of 3 to bind small molecules and show relative binding strengths that follow the trend CO ? O₂ > N₂ > H₂.