Hyperpolarization‐enhanced magnetic resonance imaging can be used to study biomolecular processes in the body, but typically requires nuclei such as 13C, 15N, or 129Xe due to their long spin‐polarization lifetimes and the absence of a proton‐background signal from water and fat in the images. Here we present a novel type of 1H imaging, in which hyperpolarized spin order is locked in a nonmagnetic long‐lived correlated (singlet) state, and is only liberated for imaging by a specific biochemical reaction. In this work we produce hyperpolarized fumarate via chemical reaction of a precursor molecule with para‐enriched hydrogen gas, and the proton singlet order in fumarate is released as antiphase NMR signals by enzymatic conversion to malate in D2O. Using this model system we show two pulse sequences to rephase the NMR signals for imaging and suppress the background signals from water. The hyperpolarization‐enhanced 1H‐imaging modality presented here can allow for hyperpolarized imaging without the need for low‐abundance, low‐sensitivity heteronuclei.
Formaldehyde reacts with solvents that contain hydroxyl groups (R-OH) in oligomerization reactions to oxymethylene oligomers (R-(OCH 2 ) n -OH). The chemical equilibria of these reactions have been studied in the literature for water, for the mono-alcohols methanol, ethanol, and 1-butanol, as well as for the diols ethylene glycol and 1,4butynediol. In the present work, the collective data were analyzed. It was found that the prolongation of the oxymethylene chains by the addition of formaldehyde can be described very well with a generalized chemical equilibrium constant K R-OHx,n≥2 , which is independent of the substructure (R) of the solvent. This holds for the oligomerization reactions leading to R-(OCH 2 ) n -OH with n ≥ 2. The chemical equilibrium constantof the reaction of formaldehyde with the solvent R-OH depends on the solvent, but simple trends are observed. The hypotheses of the existence of a generalized chemical equilibrium constant K R-OH x,n≥2 was tested for the reactions of formaldehyde with ethanol and 1-propanol, for which neither K R-OHx,1 nor K R-OHx,n were previously available.The corresponding equilibria were studied by 13 C NMR spectroscopy and the equilibrium constants were determined. A novel method was developed and used in these studies to obtain data on K R-OHx,1 by NMR spectroscopy, which is difficult due to the low amount of molecular formaldehyde. It was found that the generalized equilibrium constant is even valid for the acid-catalyzed formation of poly(oxymethylene) dimethyl ethers (OME).
Analysis of a fast-flowing liquid with NMR spectroscopy is challenging because short residence times in the magnetic field of the spectrometer result in inefficient polarization buildup and thus poor signal intensity. This is particularly problematic for benchtop NMR spectrometers because of their compact design. Therefore, in the present work, different methods to counteract this prepolarization problem in benchtop NMR spectroscopy were studied experimentally. The tests were carried out with an equimolar acetonitrile + water mixture flowing through a capillary with a 0.25 mm inner diameter at flow rates up to 2.00 mL min–1, corresponding to mean velocities of up to 0.7 m s–1. Established approaches gave only poor results at high flow rates, namely, using a prepolarization magnet, using a loopy flow cell, and using a T 1 relaxation agent. To overcome this, signal enhancement by Overhauser dynamic nuclear polarization (ODNP) was used, which is based on polarization transfer from unpaired electron spins to nuclear spins and happens on very short time scales, resulting in high signal enhancements, also in fast-flowing liquids. A corresponding setup was developed and used for the studies: the line leading to the 1 T benchtop NMR spectrometer first passes through a fixed bed with a radical matrix placed in a Halbach magnet equipped with a microwave cavity to facilitate the spin transfer. With this ODNP setup, excellent results were obtained even for the highest studied flow rates. This shows that ODNP is an enabler for fast-flow benchtop NMR spectroscopy.
Formaldehyde reacts with solvents that contain hydroxyl groups (R–OH) in oligomerization reactions to oxymethylene oligomers (R–(OCH2)n–OH). The chemical equilibria of these reactions have been studied in the literature for water, for the mono-alcohols methanol, ethanol, and 1-butanol, as well as for the diols ethylene glycol and 1,4-butynediol. In the present work, the collective data were analyzed. It was found that the prolongation of the oxymethylene chains by the addition of formaldehyde can be described very well with a generalized chemical equilibrium constant Kx,n≥2R–OH, which is independent of the substructure (R) of the solvent. This holds for the oligomerization reactions leading to R–(OCH2)n–OH with n ≥ 2. The chemical equilibrium constant Kx,1R–OH of the reaction of formaldehyde with the solvent R–OH depends on the solvent, but simple trends are observed. The hypotheses of the existence of a generalized chemical equilibrium constant Kx,n≥2R–OH was tested for the reactions of formaldehyde with ethanol and 1-propanol, for which neither Kx,1R–OH nor Kx,nR–OH was previously available. The corresponding equilibria were studied by 13C NMR spectroscopy and the equilibrium constants were determined. A novel method was developed and used in these studies to obtain data on Kx,1R–OH by NMR spectroscopy, which is difficult because of the low amount of molecular formaldehyde. It was found that the generalized equilibrium constant is even valid for the acid-catalyzed formation of poly(oxymethylene) dimethyl ethers (OME).
Hyperpolarization-enhanced magnetic resonance imaging can be used to study biomolecular processes in the body, but typically requires nuclei such as <sup>13</sup>C, <sup>15</sup>N, or <sup>129</sup>Xe due to their long spin‑polarization lifetimes and the absence of a proton‑background signal from water and fat in the images. Here we present a novel type of <sup>1</sup>H imaging, in which hyperpolarized spin order is locked in a nonmagnetic long-lived correlated (singlet) state, and is only liberated for imaging by a specific biochemical reaction. In this work we produce hyperpolarized fumarate via chemical reaction of a precursor molecule with <i>para</i>-enriched hydrogen gas, and the proton singlet order in fumarate is released as antiphase NMR signals by enzymatic conversion to malate in D<sub>2</sub>O. Using this model system we show two pulse sequences to rephase the NMR signals for imaging and suppress the background signals from water. The hyperpolarization-enhanced <sup>1</sup>H‑imaging modality presented here can allow for hyperpolarized imaging without the need for low‑abundance, low‑sensitivity heteronuclei.
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