“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.     

Single‐Scan Multidimensional NMR Analysis of Mixtures at Sub‐Millimolar Concentrations by using SABRE Hyperpolarization

Signal amplification by reversible exchange (SABRE) is a promising method to increase the sensitivity of nuclear magnetic resonance (NMR) experiments. However, SABRE‐enhanced ¹H NMR signals are short lived, and SABRE is often used to record 1D NMR spectra only. When the sample of interest is a complex mixture, this results in severe overlaps for ¹H spectra. In addition, the use of a co‐substrate, whose signals may obscure the ¹H spectra, is currently the most efficient way to lower the detection limit of SABRE experiments. Here, we describe an approach to obtain clean, SABRE‐hyperpolarized 2D ¹H NMR spectra of mixtures of small molecules at sub‐millimolar concentrations in a single scan. The method relies on the use of para‐hydrogen together with a deuterated co‐substrate for hyperpolarization and ultrafast 2D NMR for acquisition. It is applicable to all substrates that can be polarized with SABRE.     

Heterogeneous Microtesla SABRE Enhancement of 15N NMR Signals

The hyperpolarization of heteronuclei via signal amplification by reversible exchange (SABRE) was investigated under conditions of heterogeneous catalysis and microtesla magnetic fields. Immobilization of [IrCl(COD)(IMes)], [IMes=1,3‐bis(2,4,6‐trimethylphenyl), imidazole‐2‐ylidene; COD=cyclooctadiene] catalyst onto silica particles modified with amine linkers engenders an effective heterogeneous SABRE (HET‐SABRE) catalyst that was used to demonstrate a circa 100‐fold enhancement of ¹⁵N NMR signals in ¹⁵N‐pyridine at 9.4 T following parahydrogen bubbling within a magnetic shield. No ¹⁵N NMR enhancement was observed from the supernatant liquid following catalyst separation, which along with XPS characterization supports the fact that the effects result from SABRE under heterogeneous catalytic conditions. The technique can be developed further for producing catalyst‐free agents via SABRE with hyperpolarized heteronuclear spins, and thus is promising for biomedical NMR and MRI applications.     

A New Ir‐NHC Catalyst for Signal Amplification by Reversible Exchange in D2O

NMR signal amplification by reversible exchange (SABRE) has been observed for pyridine, methyl nicotinate, N‐methylnicotinamide, and nicotinamide in D₂O with the new catalyst [Ir(Cl)(IDEG)(COD)] (IDEG=1,3‐bis(3,4,5‐tris(diethyleneglycol)benzyl)imidazole‐2‐ylidene). During the activation and hyperpolarization steps, exclusively D₂O was used, resulting in the first fully biocompatible SABRE system. Hyperpolarized ¹H substrate signals were observed at 42.5 MHz upon pressurizing the solution with parahydrogen at close to the Earth's magnetic field, at concentrations yielding barely detectable thermal signals. Moreover, 42‐, 26‐, 22‐, and 9‐fold enhancements were observed for nicotinamide, pyridine, methyl nicotinate, and N‐methylnicotinamide, respectively, in conventional 300 MHz studies. This research opens up new opportunities in a field in which SABRE has hitherto primarily been conducted in CD₃OD. This system uses simple hardware, leaves the substrate unaltered, and shows that SABRE is potentially suitable for clinical purposes.     

Level Anti‐Crossings are a Key Factor for Understanding para‐Hydrogen‐Induced Hyperpolarization in SABRE Experiments

Various hyperpolarization methods are able to enhance the sensitivity of nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI) by several orders of magnitude. Among these methods are para‐hydrogen‐induced polarization (PHIP) and signal amplification by reversible exchange (SABRE), which exploit the strong nuclear alignment of para‐hydrogen. Several SABRE experiments have been reported but, so far, it has not been possible to account for the experimentally observed sign and magnetic‐field dependence of substrate polarization. Herein, we present an analysis based on level anti‐crossings (LACs), which provides a complete understanding of the SABRE effect. The field‐dependence of both net and anti‐phase polarization is measured for several ligands, which can be reproduced by the theory. The similar SABRE field‐dependence for different ligands is also explained. In general, the LAC concept allows complex spin dynamics to be unraveled, and is crucial for optimizing the performance of novel hyperpolarization methods in NMR and MRI techniques.     

Investigation of the Catalytic Activity of a 2‐Phenylidenepyridine Palladium(II) Complex Bearing 4,5‐Dicyano‐1,3‐bis(mesityl)imidazol‐2‐ylidene in the Mizoroki‐Heck Reaction

The phenylidenepyridine (ppy) palladacycles [PdCl(ppy)(IMes)] ( 4 ) [IMes = 1,3‐bis(mesityl)imidazol‐2‐ylidene] and [PdCl(ppy){(CN)₂IMes}] ( 6 ) [(CN)₂IMes = 4,5‐dicyano‐1,3‐bis(mesityl)imidazol‐2‐ylidene] were prepared by facile two step syntheses, starting with the reaction of palladium(II) chloride with 2‐phenylpyridine followed by subsequent addition of the NHC ligand to the precatalyst precursor [PdCl(ppy)]₂. Suitable crystals for the X‐ray analysis of the complexes 4 and 6 were obtained. It was shown that 6 has a shorter NHC‐palladium bond than the IMes complex 4 . The difference of the palladium carbene bond lengths based on the higher π‐acceptor strength of (CN)₂IMes in comparison to IMes. Thus, (CN)₂IMes should stabilize the catalytically active central palladium atom better than IMes. As a measure for the π‐acceptor strength of (CN)₂IMes compared to IMes, the selone (CN)₂IMes · Se ( 7 ) was prepared and characterized by ⁷⁷Se‐NMR spectroscopy. The π‐acceptor strength of 7 was illuminated by the shift of its ⁷⁷Se‐NMR signal. The ⁷⁷Se‐NMR signal of 7 was shifted to much higher frequencies than the ⁷⁷Se‐NMR signal of IMes · Se. Catalytic experiments using the Mizoroki‐Heck reaction of aryl chlorides with n‐butyl acrylate showed that 6 is the superior performer in comparison to 4 . Using complex 6 , an extensive substrate screening of 26 different aryl bromides with n‐butyl acrylate was performed. Complex 6 is a suitable precatalyst for para‐substituted aryl bromides. The catalytically active species was identified by mercury poisoning experiments to be palladium nanoparticles.     

Hyperpolarization of Pyridyl Fentalogues by Signal Amplification By Reversible Exchange (SABRE)

Fentanyl, also known as ‘jackpot’, is a synthetic opiate that is 50–100 times more potent than morphine. Clandestine laboratories produce analogues of fentanyl, known as fentalogues to circumvent legislation regarding its production. Three pyridyl fentalogues were synthesized and then hyperpolarized by signal amplification by reversible exchange (SABRE) to appraise the forensic potential of the technique. A maximum enhancement of -168-fold at 1.4 T was recorded for the ortho pyridyl ¹H nuclei. Studies of the activation parameters for the three fentalogues revealed that the ratio of ligand loss trans to hydride and hydride loss in the complex [Ir(IMes)(L)₃(H)₂]⁺ (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene) ranged from 0.52 to 1.83. The fentalogue possessing the ratio closest to unity produced the largest enhancement subsequent to performing SABRE at earth's magnetic field. It was possible to hyperpolarize a pyridyl fentalogue selectively from a matrix that consisted largely of heroin (97 : 3 heroin:fentalogue) to validate the use of SABRE as a forensic tool.     

In Situ and Ex Situ Low‐Field NMR Spectroscopy and MRI Endowed by SABRE Hyperpolarization

By using 5.75 and 47.5 mT nuclear magnetic resonance (NMR) spectroscopy, up to 10⁵‐fold sensitivity enhancement through signal amplification by reversible exchange (SABRE) was enabled, and subsecond temporal resolution was used to monitor an exchange reaction that resulted in the buildup and decay of hyperpolarized species after parahydrogen bubbling. We demonstrated the high‐resolution low‐field proton magnetic resonance imaging (MRI) of pyridine in a 47.5 mT magnetic field endowed by SABRE. Molecular imaging (i.e. imaging of dilute hyperpolarized substances rather than the bulk medium) was conducted in two regimes: in situ real‐time MRI of the reaction mixture (in which pyridine was hyperpolarized), and ex situ MRI (in which hyperpolarization decays) of the liquid hyperpolarized product. Low‐field (milli‐Tesla range, e.g. 5.75 and 47.5 mT used in this study) parahydrogen‐enhanced NMR and MRI, which are free from the limitations of high‐field magnetic resonance (including susceptibility‐induced gradients of the static magnetic field at phase interfaces), potentially enables new imaging applications as well as differentiation of hyperpolarized chemical species on demand by exploiting spin manipulations with static and alternating magnetic fields.     

“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.     

1‐(2‐Hydroxyethyl)‐3‐nitro‐1, 2, 4‐triazole and its Complexes with Copper(II) Chloride and Copper(II) Perchlorate

1‐(2‐Hydroxyethyl)‐3‐nitro‐1, 2, 4‐triazole (hnt), prepared by alkylation of 3‐nitro‐1, 2, 4‐triazole with 2‐chloroethanol, was found to react with copper(II) chloride and copper(II) perchlorate in acetonitrile/ethanol solutions giving complexes [Cu₂(hnt)₂Cl₄(H₂O)₂] and[Cu(hnt)₂(H₂O)₃](ClO₄)₂, respectively. They are the first examples of coordination compounds with a neutral N‐substituted 3‐nitro‐1, 2, 4‐triazole ligand. 1‐(2‐Hydroxyethyl)‐3‐nitro‐1, 2, 4‐triazole and the obtained complexes were characterized by NMR and IR spectroscopy, X‐ray, and thermal analyses. [Cu₂(hnt)₂Cl₄(H₂O)₂] presents a dinuclear chlorido‐bridged complex in which hnt acts as a chelating bidentate ligand, coordinated to the metal by a nitrogen atom of the triazole ring and an oxygen atom of the nitro group, and the copper atoms are inconsiderably distorted octahedral coordination. [Cu(hnt)₂(H₂O)₃](ClO₄)₂comprises a mononuclear complex cation, in which two nitrogen atoms of two hnt ligands in trans configuration and three water oxygen atoms form a square pyramidal environment around the copper atom, which is completed to an distorted octahedron with a bifurcated vertex due to two additional elongated Cu–O bonds with two nitro groups. In both complexes, Cu–O bonds with the nitro groups may be considered as semi‐coordinated.     

Hyperpolarisation of Mirfentanil by SABRE in the Presence of Heroin

Mirfentanil, a fentanyl derivative that is a μ-opioid partial agonist, is hyperpolarised via Signal Amplification By Reversible Exchange (SABRE), a para-hydrogen-based technique. [Ir(IMes)(COD)Cl] (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene, COD=cyclooctadiene) was employed as the polarisation transfer catalyst. Following polarisation transfer at 6.5 mT, the pyrazine-protons were enhanced by 78-fold (polarisation, P=0.04 %). The complex [Ir(IMes)(H)₂(mirfentanil)₂(MeOH)]⁺ is proposed to form based on the observation of two hydrides at δ −22.9 (trans to mirfentanil) and −24.7 (trans to methanol). In a mixture of mirfentanil and heroin, the former could be detected using SABRE at concentrations less than 1 % w/w. At the lowest concentration analyzed, the amount of mirfentanil present was 0.18 mg (812 μM) and produced a signal enhancement of −867-fold (P=0.42 %). following polarisation transfer at 6.5 mT.     

Fluorination Reactions at a Platinum Carbene Complex: Reaction Routes to SF3, S(=O)F and Fluorido Complexes

The electron-rich Pt complex [Pt(IMes)₂] (IMes: [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolinylidine]) can be used as precursor for the syntheses of a variety of fluorido ligand containing compounds. The sulfur fluoride SF₄ undergoes a rapid oxidative addition at Pt⁰ to yield trans-[Pt(F)(SF₃)(IMes)₂]. A photolytic reaction of SF₆ at [Pt(IMes)₂] in the presence of IMes gave the fluorido complexes trans-[Pt(F)₂(IMes)₂] and trans-[Pt(F)(SF₃)(IMes)₂] along with trans-[Pt(F)(SOF)(IMes)₂] and trans-[Pt(F)(IMes’)(IMes)] (IMes’: cyclometalated IMes ligand), the latter being products produced by reaction with adventitious water. trans-[Pt(F)(SOF)(IMes)₂] and trans-[Pt(F)₂(IMes)₂] were synthesized independently by treatment of [Pt(IMes)₂] with SOF₂ or XeF₂. A reaction of [Pt(IMes)₂] with a HF source gave trans-[Pt(H)(F)(IMes)₂], and an intermediate bifluorido complex trans-[Pt(H)(FHF)(IMes)₂] was identified. Compound trans-[Pt(H)(F)(IMes)₂] converts in the presence of CsF into trans-[Pt(F)(IMes’)(IMes)].     

Identification of Pt(II) and Pd(II) stereoisomeric complexes with aminobutyric acid by NMR and IR spectroscopy

Complexes of Pd(II) with aminobutyric acid AmH = NH₂CH(CH₂CH₃)COOH, namely, trans-[Pd(AmH)₂Cl₂] with monodentate (via the NH₂ group) AmH ligands and cis-, trans-Pd(Am)₂ with bidentate (via NH₂ and COO groups) ligands have been synthesized for the first time. Elemental analysis and IR and NMR spectroscopy were used to identify the synthesized compounds. The NMR spectra of the Pd(II) complexes were interpreted by comparing them with the NMR spectra of the analogous complexes of Pt(II). For Pt(II) and Pd(II) complexes with aminobutyric acid used as examples, an approach to identification of diastereomer bis-aminoacid complexes in specimens with racemic aminoacids by NMR spectroscopy is demonstrated.     

Investigating pyridazine and phthalazine exchange in a series of iridium complexes in order to define their role in the catalytic transfer of magnetisation from para-hydrogen

The reaction of [Ir(IMes)(COD)Cl], [IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, COD = 1,5-cyclooctadiene] with pyridazine (pdz) and phthalazine (phth) results in the formation of [Ir(COD)(IMes)(pdz)]Cl and [Ir(COD)(IMes)(phth)]Cl. These two complexes are shown by nuclear magnetic resonance (NMR) studies to undergo a haptotropic shift which interchanges pairs of protons within the bound ligands. When these complexes are exposed to hydrogen, they react to form [Ir(H)₂(COD)(IMes)(pdz)]Cl and [Ir(H)₂(COD)(IMes)(phth)]Cl, respectively, which ultimately convert to [Ir(H)₂(IMes)(pdz)₃]Cl and [Ir(H)₂(IMes)(phth)₃]Cl, as the COD is hydrogenated to form cyclooctane. These two dihydride complexes are shown, by NMR, to undergo both full N-heterocycle dissociation and a haptotropic shift, the rates of which are affected by both steric interactions and free ligand pK_a values. The use of these complexes as catalysts in the transfer of polarisation from para-hydrogen to pyridazine and phthalazine via signal amplification by reversible exchange (SABRE) is explored. The possible future use of drugs which contain pyridazine and phthalazine motifs as in vivo or clinical magnetic resonance imaging probes is demonstrated; a range of NMR and phantom-based MRI measurements are reported.     

Rhenium(I) Polypyridine Diamine Complexes as Intracellular Phosphorogenic Sensors: Synthesis,Characterization, Emissive Behavior,Biological Properties,and Nitric Oxide Sensing

We report the development of a series of rhenium(I) polypyridine complexes appended with an electron‐rich diaminoaromatic moiety as phosphorogenic sensors for nitric oxide (NO). The diamine complexes [Re(N^N)(CO)₃(py‐DA)][PF₆] (py‐DA=3‐(N‐(2‐amino‐5‐methoxyphenyl)aminomethyl)pyridine; N^N=1,10‐phenanthroline (phen) ( 1 a ), 3,4,7,8‐tetramethyl‐1,10‐phenanthroline (Me₄‐phen) ( 2 a ), 4,7‐diphenyl‐1,10‐phenanthroline (Ph₂‐phen) ( 3 a )) have been synthesized and characterized. In contrast to common rhenium(I) diimines, these diamine complexes were very weakly emissive due to quenching of the triplet metal‐to‐ligand charge‐transfer (³MLCT) emission by the diaminoaromatic moiety through photoinduced electron transfer (PET). Upon treatment with NO, the complexes were converted into the triazole derivatives [Re(N^N)(CO)₃(py‐triazole)][PF₆] (py‐triazole=3‐((6‐methoxybenzotriazol‐1‐yl)methyl)pyridine; N^N=phen ( 1 b ), Me₄‐phen ( 2 b ), Ph₂‐phen ( 3 b )), resulting in significant emission enhancement (I/I₀≈60). The diamine complexes exhibited high reaction selectivity to NO, and their emission intensity was found to be independent on pH. Also, these complexes were effectively internalized by HeLa cells and RAW264.7 macrophages with negligible cytotoxicity. Additionally, the use of complex 3 a as an intracellular phosphorogenic sensor for NO has been demonstrated.     

Structural correlations for 1H, 13C and 15N NMR coordination shifts in Au(III), Pd(II) and Pt(II) chloride complexes with lutidines and collidine

¹H, ¹³C and ¹⁵N NMR studies of gold(III), palladium(II) and platinum(II) chloride complexes with dimethylpyridines (lutidines: 2,3‐lutidine, 2,3lut; 2,4‐lutidine, 2,4lut; 3,5‐lutidine, 3,5lut; 2,6‐lutidine, 2,6lut) and 2,4,6‐trimethylpyridine (2,4,6‐collidine, 2,4,6col) having general formulae [AuLCl₃], trans‐[PdL₂Cl₂] and trans‐/cis‐[PtL₂Cl₂] were performed and the respective chemical shifts (δ^1H, δ^13C, δ^15N) reported. The deshielding of protons and carbons, as well as the shielding of nitrogens was observed. The ¹H, ¹³C and ¹⁵N NMR coordination shifts (Δ^1H_coord, Δ^13C_coord, Δ^15N_coord; Δ_coord = δ_complex ? δ_ligand) were discussed in relation to some structural features of the title complexes, such as the type of the central atom [Au(III), Pd(II), Pt(II)], geometry (trans‐ or cis‐), metal‐nitrogen bond lengths and the position of both methyl groups in the pyridine ring system. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis,Characterization, Catalytic and Antibacterial Activity of Two Series of Dinuclear Ruthenium Sulphoxide Complexes Using 5,5¢‐Methylenebis(pyridine) as Bis‐chelating Bridging Ligand

The reaction of a new heterocyclic bidentate N containing spacer, (ligand) 5,5′‐methylenebis(pyridine) with ruthenium sulphoxide precursors resulted, dinuclear complexes. We herein report three formulations; [{cis,fac‐RuCl₂(so)₃}₂(μ‐mbp)].3so; [{trans,mer‐RuCl₂(so)₃₂}₂(μ‐mbp)].3so and [{trans‐RuCl₄(so)}₂(μ‐mbp)]^2?[X]₂⁺; where so = dimethyl‐sulfoxide/tetramethylenesulfoxide; mbp = 5,5′‐methylenebis(pyridine) and [X]⁺ = [(dmso)₂H]⁺, Na⁺ or [(tmso)H]⁺. These complexes were characterized on the basis of elemental analyses, molar conductance measurement, magnetic susceptibility, FT‐IR, ¹H‐NMR, ¹³C{¹H}‐NMR, electronic spectroscopy and FAB‐Mass spectrometry. Catalytic activity of these complexes has been investigated in hydrolysis of benzonitrile. All the complexes exhibit good antibacterial activity against gram‐negative bacteria Escherichia coli in comparison to Chloramphenicol.     

Computational (DFT) and Experimental (NMR) Study of the Chelation of an Iridium Hyperpolarization Transfer Catalyst by Amino Acids

Non-hydrogenative Para-Hydrogen Induced Hyperpolarization (nhPHIP) is a Nuclear Magnetic Resonance (NMR) hyperpolarization technique which has experimentally been used to analyze complex biological samples containing amino acids using the Ir-IMes hyperpolarization transfer catalyst. A computational study based on Density Function Theory (DFT) was performed on all relevant stereoisomers of [Ir(H)₂(IMes)(AA)(Py)] (with AA=glycine, alanine, valine; Py=pyridine), for which R/S chirality and orientation of the amino acid chelation (C/A) were considered. A total of 30 structures were calculated comprising of 6 stereoisomers for achiral glycine, and 12 stereoisomers for each of the chiral amino acids. The abundances derived from the DFT energies confirmed the trends observed in thermal (non-hyperpolarized) NMR experiments. Additionally, theoretical calculations of electronic (Wiberg bond indices, Natural Bond Orders, Frontier Orbital Analysis), bond dissociation energies, transition states, and activation energies related to interconversion between binding modes, and steric factors (Solid angle) were performed to provide detailed explanations for NMR experimental observations.     

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.