This perspective article provides an assessment of the state-of-the-art in the molecular-resolution analysis of complex organic materials. These materials can be divided into biomolecules in complex mixtures (which are amenable to successful separation into unambiguously defined molecular fractions) and complex nonrepetitive materials (which cannot be purified in the conventional sense because they are even more intricate). Molecular-level analyses of these complex systems critically depend on the integrated use of high-performance separation, high-resolution organic structural spectroscopy and mathematical data treatment. At present, only high-precision frequency-derived data exhibit sufficient resolution to overcome the otherwise common and detrimental effects of intrinsic averaging, which deteriorate spectral resolution to the degree of bulk-level rather than molecular-resolution analysis. High-precision frequency measurements are integral to the two most influential organic structural spectroscopic methods for the investigation of complex materials—NMR spectroscopy (which provides unsurpassed detail on close-range molecular order) and FTICR mass spectrometry (which provides unrivalled resolution)—and they can be translated into isotope-specific molecular-resolution data of unprecedented significance and richness. The quality of this standalone de novo molecular-level resolution data is of unparalleled mechanistic relevance and is sufficient to fundamentally advance our understanding of the structures and functions of complex biomolecular mixtures and nonrepetitive complex materials, such as natural organic matter (NOM), aerosols, and soil, plant and microbial extracts, all of which are currently poorly amenable to meaningful target analysis. The discrete analytical volumetric pixel space that is presently available to describe complex systems (defined by NMR, FT mass spectrometry and separation technologies) is in the range of 108–14 voxels, and is therefore capable of providing the necessary detail for a meaningful molecular-level analysis of very complex mixtures. Nonrepetitive complex materials exhibit mass spectral signatures in which the signal intensity often follows the number of chemically feasible isomers. This suggests that even the most strongly resolved FTICR mass spectra of complex materials represent simplified (e.g. isomer-filtered) projections of structural space.

https://link.springer.com/content/pdf/10.1007%2Fs00216-007-1577-4.pdf

High-precision frequency measurements: indispensable tools at the core of the molecular-level analysis of complex systems.

http://files.tk-team-iquir.webnode.com/200000022-6a21c6b1ab/J%20Pharm%20Biomed%20Anal%202014%20101%20102.pdf

Pharmaceutical impurities and degradation products: Uses and applications of NMR techniques

Nuclear magnetic resonance (NMR) spectroscopy is one of the most important and powerful instrumental analytical techniques for structural elucidation of unknown small and large (complex) isolated and synthesized compounds in organic and inorganic chemistry. X-ray crystallography, neutron scattering (neutron diffraction), and NMR spectroscopy are the only suitable methods for three-dimensional structure determination at atomic resolution. Moreover, these methods are complementary. However, by means of NMR spectroscopy, reaction dynamics and interaction processes can also be investigated. Unfortunately, this technique is very insensitive in comparison with other spectrometric (e.g., mass spectrometry) and spectroscopic (e.g., infrared spectroscopy) methods. Mainly through the development of stronger magnets and more sensitive solenoidal microcoil flow probes, this drawback has been successfully counteracted. Capillary NMR spectroscopy increases the mass-based sensitivity of the NMR spectroscopic analysis up to 100-fold compared with conventional 5-mm NMR probes, and thus can be coupled online and off-line with other microseparation and detection techniques. It offers not only higher sensitivity, but in many cases provides better quality spectra than traditional methods. Owing to the immense number of compounds (e.g., of natural product extracts and compound libraries) to be examined, single microcoil flow probe NMR spectroscopy will soon be far from being sufficiently effective as a screening method. For this reason, an inevitable trend towards coupled microseparation–multiple microcoil flow probe NMR techniques, which allow simultaneous online and off-line detection of several compounds, will occur. In this review we describe the current status and possible future developments of single and multiple microcoil capillary flow probe NMR spectroscopy and its application as a high-throughput tool for the analysis of a large number of mass-limited samples. The advantages and drawbacks of different coupled microseparation–capillary NMR spectroscopy techniques, such as capillary high-performance liquid chromatography–NMR spectroscopy, capillary electrophoresis–NMR spectroscopy, and capillary gas chromatography–NMR spectroscopy, are discussed and demonstrated by specific applications. Another subject of discussion is the progress in parallel NMR detection techniques. Furthermore, the applicability and mixing capability of tiny reactor systems, termed “microreactors” or “micromixers,” implemented in NMR probes is demonstrated by carbamate- and imine-forming reactions.

From single to multiple microcoil flow probe NMR and related capillary techniques: a review

Development of a high-field NMR magnet has been underway at the Tsukuba Magnet Laboratory of the National Institute for Materials Science. The magnet succeeded in a persistent-mode operation at 21.17 T in December 1999. A 283-day long-term operation was carried out from October 2000 to August 2001. It included a persistent operation at 21.6 T (920 MHz) for 108 days. This was the highest field that the superconducting magnets have ever achieved in a persistent operation. Field decay was less than 2 Hz/h. Field homogeneity after correcting with superconducting shim coils were less than 0.1 ppm in a sample volume. These results confirmed that this magnet had been successfully developed as a high-resolution NMR magnet.

Persistent-mode operation of a 920 MHz high-resolution NMR magnet

Molecular spectroscopic detection plays a crucial role in gas chromatography (GC). Some detectors constitute element-selective spectroscopy, where an element-containing species generates the detected signal, e.g. flame photometric detection (S, P, Cu); chemiluminescence detection (S, N). These respond with selective response, usually with excellent analyte detectability and reduced matrix interferences. Classical molecular spectroscopic detectors – Fourier transform infrared, nuclear magnetic resonance, ultraviolet – respond by giving a spectrum characteristic of the (intact) molecule. Molecular structure response plays multi-faceted roles: it produces a unique spectrum of a molecule, provided it is resolved by the column and presented to the detector as a single compound; or the chromatogram can be generated by responding to the total signal, or selectively to a given component of the signal. This review summarises the response, sensitivities, applicability, and recent literature reports of molecular spectroscopic detection. Hyphenation with dual detection and brief comments on multidimensional GC is included.

Molecular spectroscopy – Information rich detection for gas chromatography

Development and testing of superfluid-cooled 900 MHz NMR magnet

The first 920 MHz high-resolution NMR magnet has been operating at the Tsukuba Magnet Laboratory (TML) of the National Institute for Materials Science since April 2002. It has proved its effectiveness by determining the three-dimensional structures of protein molecules. To accelerate studies in structural biology and solid-state NMR, a second high-field NMR magnet was developed and installed at TML. Although its basic design was based on that of the 920 MHz NMR magnet, some parts have been improved. We applied a 16 wt.% Sn bronze-processed (Nb,Ti)3Sn conductor for the innermost coil, replacing the 15 wt.% Sn conductor. This enabled a size reduction of 3.50 mm x 1.75 mm in the first magnet to 2.80 mm x 1.83 mm in the second because of an improvement of more than 20% in critical current density. As the magnetic field generated by the innermost coil was increased, at the same operating current of the first magnet, operation at 930 MHz was expected. The magnet was energized up to 21.6 T without any quenching and operated in a persistent mode at 920 MHz for more than one month. On March 24, 2004, it was excited up to 930 MHz. After the central field was increased to 21.89 T once, it was decreased to 21.86 T, and the persistent-mode operation started from a frequency of 930.7 MHz. This is the highest field that the magnets made of NbTi and Nb3Sn coils have ever achieved. The field stability and the field homogeneity were measured and it was confirmed that this magnet can be applied as an NMR magnet.

https://www.jstage.jst.go.jp/article/jcsj/39/12/39_12_625/_pdf

Development of a 930 MHz NMR Magnet

We studied magnetizations of over-doped Bi 2 Sr 2 CaCu 2 O 8+ y single crystals The thermoremanent magnetization shows an anomalous random oscillation in low frequency modulation field below 20 K The result indicates a random motion of the vortices, which suggest there exists a new magnetic phase in the vortex solid phase

Akio Sato

Papers

Development and testing of superfluid-cooled 900 MHz NMR magnet

Development of a 930 MHz NMR Magnet

Anomaly of ac susceptibility in low temperature for over-doped Bi2Sr2CaCu2O8+y