Inside Cover: Parahydrogen-Induced Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation (Angew. Chem. Int. Ed. 5/2023)

The feasibility of Carbon-13 Radiofrequency (RF) Amplification by Stimulated Emission of Radiation (C-13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1-¹³C]acetate. Hyperpolarized ethyl [1-¹³C]acetate was prepared via pairwise addition of parahydrogen to vinyl [1-¹³C]acetate and polarization transfer from nascent parahydrogen-derived protons to the carbon-13 nucleus via magnetic field cycling yielding C-13 nuclear spin polarization of approximately 6 %. RASER signals were detected from samples with concentration ranging from 0.12 to 1 M concentration using a non-cryogenic 1.4T NMR spectrometer equipped with a radio-frequency detection coil with a quality factor (Q) of 32 without any modifications. C-13 RASER signals were observed for several minutes on a single bolus of hyperpolarized substrate to achieve 21 mHz NMR linewidths. The feasibility of creating long-lasting C-13 RASER on biomolecular carriers opens a wide range of new opportunities for the rapidly expanding field of C-13 magnetic resonance hyperpolarization.     

Parahydrogen-Induced Radio Amplification by Stimulated Emission of Radiation

Radio amplification by stimulated emission of radiation (RASER) was recently discovered in a low-field NMR spectrometer incorporating a highly specialized radio-frequency resonator, where a high degree of proton-spin polarization was achieved by reversible parahydrogen exchange. RASER activity, which results from the coherent coupling between the nuclear spins and the inductive detector, can overcome the limits of frequency resolution in NMR. Here we show that this phenomenon is not limited to low magnetic fields or the use of resonators with high-quality factors. We use a commercial bench-top 1.4 T NMR spectrometer in conjunction with pairwise parahydrogen addition producing proton-hyperpolarized molecules in the Earth's magnetic field (ALTADENA condition) or in a high magnetic field (PASADENA condition) to induce RASER without any radio-frequency excitation pulses. The results demonstrate that RASER activity can be observed on virtually any NMR spectrometer and measures most of the important NMR parameters with high precision.     

Parahydrogen‐Induced Radio Amplification by Stimulated Emission of Radiation

Radio amplification by stimulated emission of radiation (RASER) was recently discovered in a low‐field NMR spectrometer incorporating a highly specialized radio‐frequency resonator, where a high degree of proton‐spin polarization was achieved by reversible parahydrogen exchange. RASER activity, which results from the coherent coupling between the nuclear spins and the inductive detector, can overcome the limits of frequency resolution in NMR. Here we show that this phenomenon is not limited to low magnetic fields or the use of resonators with high‐quality factors. We use a commercial bench‐top 1.4 T NMR spectrometer in conjunction with pairwise parahydrogen addition producing proton‐hyperpolarized molecules in the Earth's magnetic field (ALTADENA condition) or in a high magnetic field (PASADENA condition) to induce RASER without any radio‐frequency excitation pulses. The results demonstrate that RASER activity can be observed on virtually any NMR spectrometer and measures most of the important NMR parameters with high precision.     

A comparison of electrospray-ionization and matrix-assisted laser desorption/ionization mass spectrometry with nuclear magnetic resonance spectroscopy for the characterization of synthetic copolymers

Electrospray ionization (ESI-MS) and matrix assisted laser desorption-ionization (MALDI-MS) were used to determine the composition (monomer ratios) and structure (end group analysis) relative to 1H NMR spectroscopy and theoretical predictions for three different copolymers: poly(butyl acrylate/vinyl acetate) (PBA/PVAc), poly(methyl methacrylate/vinyl acetate) (PMMA/PVAc) and poly(butyl acrylate/methyl methacrylate) (PBA/PMMA). We found that the ESI results were in excellent agreement with 1H NMR spectroscopy for PBA/PVAc and PBA/PMMA copolymers whereas there was more divergence in the case of PMMA/PVAc. In the case of PBA/PMMA copolymers similar distributions of products were observe by ESI-MS and MALDI-MS with the two major products classes differing by their end-groups. One class has hydrogen and dodecylthio end groups while in the other the dodecylthio has been replaced by alpha-cyanoisopropyl from the initiator. The relative abundance of these distributions as a function of copolymer conversion for a series of reaction conditions was investigated by both ESI and MALDI. MALDI results consistently underestimated (relative to ESI) the butylacrylate monomer ratio in PBA/PMMA and the abundance of co-polymer oligomers terminated by a dodecylthio group from the chain transfer agent.     

Solid-state NMR of endohedral hydrogen-fullerene complexes

We present an overview of solid-state NMR studies of endohedral H(2)-fullerene complexes, including (1)H and (13)C NMR spectra, (1)H and (13)C spin relaxation studies, and the results of (1)H dipole-dipole recoupling experiments. The available data involves three different endohedral H(2)-fullerene complexes, studied over a wide range of temperatures and applied magnetic fields. The symmetry of the cage influences strongly the motionally-averaged nuclear spin interactions of the endohedral H(2) species, as well as its spin relaxation behaviour. In addition, the non-bonding interactions between fullerene cages are influenced by the presence of endohedral hydrogen molecules. The review also presents several pieces of experimental data which are not yet understood, one example being the structured (1)H NMR lineshapes of endohedral H(2) molecules trapped in highly symmetric cages at cryogenic temperatures. This review demonstrates the richness of NMR phenomena displayed by H(2)-fullerene complexes, especially in the cryogenic regime.     

银催化邻炔基苯甲醛腙合成多取代异喹啉偶极子

将含有不同取代基团的邻炔基苯甲醛腙化合物在乙酸银催化下,以二氯甲烷作溶剂,室温下自身发生环化反应合成N,N-异喹啉偶极子化合物。通过质谱(MS)、核磁共振波谱仪(NMR)等技术手段表征化合物的结构。考察了不同催化剂及其用量、原料配比、溶剂、温度对反应的影响。在最优条件下,反应收率为60%,在底物适应性上最高可达到85%。该方法具有操作简单,反应条件简单温和,产物收率高以及底物适用性好等优点。本文通过对实验条件、底物适用性等方面的探索,解决了以往合成异喹啉偶极子方法学中存在的多步进行、反应温度过高、底物适应性较低等不足与缺点,为制备含此类骨架的化合物提供了新的实验方法。     

A Versatile Compact Parahydrogen Membrane Reactor

We introduce a Spin Transfer Automated Reactor (STAR) that produces continuous parahydrogen induced polarization (PHIP), which is stable for hours to days. We use the PHIP variant called signal amplification by reversible exchange (SABRE), which is particularly well suited to produce continuous hyperpolarization. The STAR is operated in conjunction with benchtop (1.1 T) and high field (9.4 T) NMR magnets, highlighting the versatility of this system to operate with any NMR or MRI system. The STAR uses semipermeable membranes to efficiently deliver parahydrogen into solutions at nano to milli Tesla fields, which enables ¹H, ¹³C, and ¹⁵N hyperpolarization on a large range of substrates including drugs and metabolites. The unique features of the STAR are leveraged for important applications, including continuous hyperpolarization of metabolites, desirable for examining steady-state metabolism in vivo, as well as for continuous RASER signals suitable for the investigation of new physics.     

超(近)临界条件下醋酸甲酯水解过程研究

超(近)临界水作为优良的有机反应溶剂适合于针对酸碱催化类型有机反应绿色工艺的开发.本课题以具备工业生产背景的醋酸甲酯水解作为研究体系,在一管式反应器中,将原料(5%质量分数)置于体系的超(近)临界条件下(523～673K,23～32MPa)进行反应操作.实验结果表明,在无外加酸性催化剂情况下,水解反应以接近1的选择性,在150～300s内达到热力学平衡限制,同时在系统临界点附近,溶剂化作用对反应动力学影响显著.根据SN2反应机理对反应动力学方程进行了回归.     

Using model complexes to augment and advance metalloproteinase inhibitor design

The tetrahedral zinc complex [(Tp(Ph,Me))ZnOH] (Tp(Ph,Me) = hydrotris(3,5-phenylmethylpyrazolyl)borate) was combined with 2-thenylmercaptan, ethyl 4,4,4-trifluoroacetoacetate, salicylic acid, salicylamide, thiosalicylic acid, thiosalicylamide, methyl salicylate, methyl thiosalicyliate, and 2-hydroxyacetophenone to form the corresponding [(Tp(Ph,Me))Zn(ZBG)] complexes (ZBG = zinc-binding group). X-ray crystal structures of these complexes were obtained to determine the mode of binding for each ZBG, several of which had been previously studied with SAR by NMR (structure-activity relationship by nuclear magnetic resonance) as potential ligands for use in matrix metalloproteinase inhibitors. The [(Tp(Ph,Me))Zn(ZBG)] complexes show that hydrogen bonding and donor atom acidity have a pronounced effect on the mode of binding for this series of ligands. The results of these studies give valuable insight into how ligand protonation state and intramolecular hydrogen bonds can influence the coordination mode of metal-binding proteinase inhibitors. The findings here suggest that model-based approaches can be used to augment drug discovery methods applied to metalloproteins and can aid second-generation drug design.     

Diffusion Spectrum of Polymer Melt Measured by Varying Magnetic Field Gradient Pulse Width in PGSE NMR

The translational motion of polymers is a complex process and has a big impact on polymer structure and chemical reactivity. The process can be described by the segment velocity autocorrelation function or its diffusion spectrum, which exhibit several characteristic features depending on the observational time scale—from the Brownian delta function on a large time scale, to complex details in a very short range. Several stepwise, more-complex models of translational dynamics thus exist—from the Rouse regime over reptation motion to a combination of reptation and tube-Rouse motion. Accordingly, different methods of measurement are applicable, from neutron scattering for very short times to optical methods for very long times. In the intermediate regime, nuclear magnetic resonance (NMR) is applicable—for microseconds, relaxometry, and for milliseconds, diffusometry. We used a variation of the established diffusometric method of pulsed gradient spin-echo NMR to measure the diffusion spectrum of a linear polyethylene melt by varying the gradient pulse width. We were able to determine the characteristic relaxation time of the first mode of the tube-Rouse motion. This result is a deviation from a Rouse model of polymer chain displacement at the crossover from a square-root to linear time dependence, indicating a new long-term diffusion regime in which the dynamics of the tube are also described by the Rouse model.     

Methoxy and Methyl Group Rotation: Solid‐State NMR 1H Spin‐Lattice Relaxation,Electronic Structure Calculations,X‐ray Diffractometry,and Scanning Electron Microscopy

We report solid‐state ¹H nuclear magnetic resonance (NMR) spin‐lattice relaxation experiments, X‐ray diffractometry, field‐emission scanning electron microscopy, and both single‐molecule and cluster ab initio electronic structure calculations on 1‐methoxyphenanthrene ( 1 ) and 3‐methoxyphenanthrene ( 2 ) to investigate the rotation of the methoxy groups and their constituent methyl groups. The electronic structure calculations and the ¹H NMR relaxation measurements can be used together to determine barriers for the rotation of a methoxy group and its constituent methyl group and to develop models for the two coupled motions.     

On ion transport regulation with field-effect nonlinear electroosmosis control in microfluidics embedding an ion-selective medium

We study herein numerically the use of induced-charge electrokinetic phenomena to enable a flexible control of ion transport of dilute electrolyte in a straight ion concentration polarization system. The effect of three convection modes of induced-charge electrokinetic phenomena, including induced-charge electroosmosis, flow-field effect transistor, and alternating-current electroosmosis (ACEO), on convective arrestment of diffusive wave-front propagation is investigated by developing a cross-scale and fully coupled transient numerical simulation model, wherein multiple frequency electrochemical polarization and nonlinear diffuse charge dynamics in spatiotemporally varying solution conductivity are taken into account. We demonstrate by detailed comparative simulation studies that ACEO vortex flow field above a metal strip array arranged along the anodic chamber's bottom surface serves as the most efficient way for adjusting the salt density distribution at micrometer and even millimeter dimension, due to its high flexibility in controlling the stirring flow state with the introduction of two extra electrical parameters. The specific operating status is determined by whether the electrode array is floating in potential (induced-charge electroosmosis) or biased to ground (flow-field effect transistor) or forced to oscillate at another Fourier mode (ACEO). These results prove useful for on-chip electric current control with electroconvective stirring.     

2H NMR studies of oriented bacteriorhodopsin membranes to determine single bond orientations

For the structural analysis of oriented polymers and other macromolecular systems, we present a solid state ²H NMR technique capable of measuring the orientations of individual chemical bond vectors with high accuracy. When an immobilized uniaxially oriented sample is aligned along the spectrometer magnetic field direction, the angle between a deuterium-labelled methyl group and the axis of ordering can be calculated from the spectral quadrupole splitting. However, since positive and negative splittings are indistinguishable, there may be two solutions. We show how these may be discriminated by acquiring additional spectra at different sample inclinations (Ref 1). The analysis of the resulting complex lineshapes is aided by computer simulation, which furthermore allows a characterization of the orientational distribution function of the sample. The ²H NMR method has been developed around the membrane protein bacteriorhodopsin as a biological model system that can be prepared in uniaxially oriented films. The overall orientation and molecular conformation of the retinal chromophore were resolved from the individual orientations of its five labelled methyl groups (Refs 2, 3). Structural changes were detected in an intermediate of the photocycle (M), which provide insight into the mechanism of the protein as a proton pump (Ref 4).     

Parahydrogen-Induced Polarization of Diethyl Ether Anesthetic

The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas-phase lifetimes of hyperpolarized ¹²⁹Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of ¹²⁹Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low-cost and high-throughput preparation of proton-hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by ¹H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas-phase T₁ relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, with T₁ of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long-lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond.     

Secondary tritium isotope effects,a useful mechanistic probe for the study of acetoxyl participation and transfer

Tritium labelling on the acetoxyl methyl group has been used to probe the mode of incorporation of acetate into cinnamyl acetate in the solvolyes of cinnamyl chloride and cinnamylmercuric acetate, and in the allylic oxidation of allylbenzene with mercuric acetate.     

Stability and solution concentration enhancement of resveratrol by solid dispersion in cellulose derivative matrices

Resveratrol is a highly biologically active phytoalexin, found in many plant materials that are common elements of the human diet, such as grapes, nuts, and red wine. The therapeutic or disease preventative potential of this natural polyphenolic antioxidant has been limited in part due to its poor aqueous solubility and low oral bioavailability. We hypothesized that solid dispersion of resveratrol (Res) in cellulose derivative matrices might afford amorphous dispersions, from which supersaturated Res solutions would be produced in the human gastrointestinal (GI) tract, resulting in higher Res bioavailability. We carried out structure–property studies employing cellulose esters with a range of physical characteristics but possessing features suitable for use in amorphous solid dispersions: carboxymethylcellulose acetate butyrate (CMCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate adipate propionate (CAAdP). The cellulose derivative results were compared with those of a negative control, pure crystalline Res, and a positive control, Res/poly(vinylpyrrolidinone) (PVP). Solid dispersions were characterized by powder X-ray diffraction (XRPD), modulated differential scanning calorimetry (MDSC), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR) of solid dispersions. HPMCAS and PVP solid dispersions afforded faster and more complete Res release at pH 6.8; however Res is also released from PVP matrices at pH 1.2. The carboxyl-containing cellulose derivatives release Res to only a small extent at pH 1.2. This combination of solution and solid phase stabilization against crystallization, and pH-triggered drug release makes these cellulose esters attractive candidates for Res bioavailability enhancement.     

胆甾-4α-甲基-8-烯-3β，7α-二醇二乙酸酯的结构与性质研究

Lophenol, cholest-4α-methyl-7-en-3β-ol (1), obtained from Dracaena cochinchinensis (Lour.) S. C. Chen, was structurally modified. It was acetylated to protect 3β-hydroxyl group, and then oxidised by selenium dioxide in acetic acid to give cholest-4a-methyl-8-en-3β, Ta-diol diacetate (3). This compound 3 is unstable in chloroform solution or when heated and easily converted to a diene compound, cholest-4a-methyl-7,14-dien-3β-ol acetate (4). The structures of 3 and 4 were elucidated by means of IR, ^1H NMR, ^13C NMR and MS, and the absolute configuration of 3 was established by X-ray crystallography. The property of 3 was also discussed in this paper. Both 3 and 4 are new compounds and were reported for the first time.     

Dielectric properties of self-assembled layers of octadecylamine on mica in dry and humid environments

Atomic force microscopy operating in noncontact electrostatic force mode was used to study the interaction of water with films of alkylamines and alkylsilanes on mica. The films efficiently block water adsorption except in exposed mica areas, where it strongly modifies the mobility of surface ions. We also studied the molecular orientation of octadecylamine molecules forming monolayers and multilayer islands. In monolayer films the molecules bind to mica through the amino group, producing a positive contact potential relative to mica (dipole pointing up). In multilayer films the methyl and amino group terminations are exposed in alternating layers that give rise to alternating values of the contact potential. These findings correlate with low and high friction forces measured in the methyl termination and amino terminations.     

Dynamics by solid-state NMR: detailed study of ibuprofen Na salt and comparison with ibuprofen

The various internal rotations and interconformational jumps of the Na-salt form of ibuprofen in the solid state were characterized in detail by means of the simultaneous analysis of a variety of low- and high-resolution NMR experiments aimed at measuring several (13)C and (1)H spectral and relaxation properties at different temperatures and frequencies. The results were first qualitatively analyzed to identify the motions of the different molecular fragments and to assign them to specific frequency regimes (slow, <10(3) Hz; intermediate, 10(3)-10(6) Hz; and fast, >10(6) Hz). Subsequently, a simultaneous fit of the experimental data sets most sensitive to each frequency range was performed by using suitable motional models, thus obtaining, for each motion, correlation times and activation energies. The motions so characterized were: the rotations of the three methyl groups and of the isobutyl group, occurring in the fast regime, and the π-flip of the phenyl ring, belonging to the intermediate motional regime. The results obtained for the Na-salt form were compared with those of the acidic form of ibuprofen, previously obtained from a similar solid-state NMR approach: despite the very similar chemical structure of the two compounds, their dynamic properties in the solid state are noticeably different.     

Unexpected shielding of methyl group protons in some piperidines

High resolution 1H and 13C NMR spectra of four 3-ethyl-4-hydroxy- 4-phenylpiperidines 1-4 have been recorded in CDCl3 and analysed. The conformations of phenyl and hydroxyl groups at C(4) and ethyl group at C(3) were analysed in detail. The chemical shift of the methyl protons in the ethyl group are quite surprising; they are close to TMS in CDCl(3) and even negative in DMSO-d6. These results are interpreted in terms of the magnetic anisotropy of the phenyl rings at C(2) and C(4) which, in turn, depend on the conformations of the ethyl group at C(3) and the hydroxyl group at C(4). Favoured conformations of ethyl group at C(3) and hydroxyl group at C(4) were calculated by AM1 methods.