Interpretation Of NMR Spectra Research Articles

13C‐Labeling as a Method in Organic Synthesis, Catalysis and Biochemical Applications

AbstractThe incorporation of a labeled 13C atom provides a plethora of opportunities in organic synthesis and catalysis. Structure of complicated compounds can be successfully confirmed using the precise location of a labeled carbon atom; a reaction mechanism can be supported by the presence or absence of a label in reaction products; metabolic pathways of biological compounds can be found out depending on labeled products; the concentration of analyzed labeled compounds can be significantly lower for recording and successful interpretation of NMR spectra, etc. This review aims to provide a researcher with common and promising strategies for the synthesis of labeled compounds so that a researcher can select an appropriate route to save valuable labeled material. All the labeling approaches were considered based on starting labeling source. Ideological aim of the review is to demonstrate the opportunities for label incorporation so that a researcher can find the improvements in his own topic using labeled compounds. Utilization of labeled compounds in catalysis and studying reaction mechanisms were also considered to demonstrate the capabilities of labeled compounds, which may be useful in specific tasks and applications. The potential of labeled compounds in bioactive compound metabolite analysis was demonstrated on selected examples.

Accelerating NMR Shielding Calculations Through Machine Learning Methods: Application to Magnesium Sodium Silicate Glasses.

In this work, we have applied the Kernel Ridge Regression (KRR) method using a Least Square Support Vector Regression (LSSVR) approach for the prediction of the NMR isotropic magnetic shielding (σiso) of active nuclei (17O, 23Na, 25Mg, and 29Si) in a series of (Mg, Na) - silicate glasses. The Machine Learning (ML) algorithm has been trained by mapping the local environment of each atom described by the Smooth Overlap of Atomic Position (SOAP) descriptor with isotropic chemical shielding values computed with DFT using the Gauge-Included-Projector-Augmented-Wave (GIPAW) approach. The influence of different training datasets generated through molecular dynamics simulations at various temperatures and with different inter-atomic potentials has been tested and we demonstrate the importance of a wide exploration of the configurational space to enhance the transferability of the ML-regressor. Finally, the trained ML-regressor has been used to simulate the 29Si MAS NMR spectra of systems containing up to 20000 atoms by averaging hundreds of configurations extracted from classical MD simulations to account for thermal vibrations. This ML approach is a powerful tool for the interpretation of NMR spectra using relatively large systems at a fraction of the computational time required by quantum mechanical calculations which are of high computational cost.

New isoindolinone derivatives isolated from the fruiting bodies of the basidiomycete Hericium coralloides

Preparative high-performance liquid chromatography (HPLC) purification of the ethyl acetate extract derived from dried basidiomes of the European mushroom Hericium coralloides led to the identification of two previously undescribed isoindolinone derivatives named corallocins D and E (1-2). The structures of the compounds were elucidated based on HR-ESI-MS (high-resolution electron spray ionization mass spectrometry), interpretation of 1D and 2D NMR spectra, electronic circular dichroism (ECD) experiments, and comparisons with published and theoretical data. The metabolites were tested for their cytotoxic and antimicrobial effects in vitro where weak to moderate biological effects were observed against HeLa cells (KB 3.1), Mucor hiemalis and Bacillus subtilis.

Relativistic DFT Calculations of Cadmium and Selenium Solid-State NMR Spectra of CdSe Nanocrystal Surfaces.

Solid-state NMR spectra have been used to probe the structure of CdSe nanocrystals and propose detailed models of their surface structures. Density functional theory (DFT)-optimized cluster models that represent probable molecular structures of carboxylate-coordinated surface sites have been proposed. However, to the best of our knowledge, 113Cd and 77Se chemical shifts have not been calculated for these surface models. We performed relativistic DFT calculations of cadmium and selenium magnetic shielding tensors on model compounds with previously measured solid-state NMR spectra with (i) the four-component Dirac-Kohn-Sham (DKS) Hamiltonian and (ii) the scalar and (iii) spin-orbit levels within the ZORA Hamiltonian. Molecular clusters with Cd and Se sites in varying bonding environments were used to model CdSe (100) and CdSe(111) surfaces capped with carboxylic acid ligands. Our calculations identify the observed 113Cd isotropic chemical shifts δ(iso) of -465, -318, and -146 ppm arising from CdSeO3, CdSe2O2, and CdSe3O surface groups, respectively, with very good agreement with experimental measurements. The 113Cd chemical shifts linearly decrease with the number of O-neighbors. The calculated spans (δ11 - δ33) encompass the experimental values for CdSe3O and CdSe2O2 clusters but are slightly larger than the measured value for CdSeO3 clusters. Relativistic DFT calculations predicted a one-bond 113Cd-77Se scalar coupling of 258 Hz, which is in good agreement with the experimental values of 250 Hz. With a dense coverage of carboxylic acid ligands, the CdSe (100) surface shows a distribution of Cd-Se bond lengths and J-couplings. Relativistic DFT simulations thus aid in interpretation of NMR spectra of CdSe nanocrystals and related nanomaterials.

Cesium Oxo-fluoro-aluminates in the CsF-Al2O3 System: Synthesis and Structural Characterization.

In an experiment combining various approaches, a precise examination of a portion of the phase diagram of a CsF-Al2O3 system was carried out up to 40 mol% Al2O3. CsF-Al2O3 solidified mixtures have been investigated using high-field solid-state NMR (133Cs, 27Al, and 19F) spectroscopy and X-ray powder diffraction over a broad range of compositions with synchrotron powder diffraction and Rietveld analysis. A new cesium oxo-fluoro-aluminate, Cs2Al2O3F2, was discovered, prepared, and structurally analyzed by synchrotron diffraction analysis. In addition to Cs2Al2O3F2, we have synthesized the following pure compounds in order to aid in the interpretation of NMR spectra of the solidified samples: CsAlF4, Cs3AlF6, and CsAlO2.

Hosimosines A-E, structurally diverse cytisine derivatives from the seeds of Ormosia hosiei Hemsl. et Wils

Ormosia hosiei Hemsl. et Wils (Fabaceae family) is an arbor species endemic to China. The seeds of O. hosiei have been used as traditional Chinese medicine to treat hernia, abdominal pain, blood stasis and amenorrhea. Cytisine-like and angustifoline type alkaloids were main components identified from this plant. In our research on the bioactive alkaloids from the promising Chinese medicinal plants, four new angustifoline type alkaloids (1–4) and a new cytisine-like alkaloid (5), named hosimosine A-E, together with 13 known analogues (6–18) were isolated from the seeds of O. hosiei. Their structures were elucidated by the extensive spectroscopic methods, especially the interpretation of NMR spectra and specific rotations, along with the methods of NMR and ECD calculation. Compounds 1–4 were identified as two pairs of epimers, whose relative configurations were deduced from density functional theory (DFT) calculations of NMR chemical shifts and DP4+ analysis, and absolute configurations were determined by comparison of their experimental and theoretical ECD spectra. Compound 5 displayed two sets of NMR data caused by the existence of tautomeric forms. Compounds 14, 17 and 18 were determined to be enantiomers of literature compounds. Some of the isolates exhibited moderate cytotoxic effects against HepG2, A2780 and MCF-7 cells.

Panaxindole, a novel indole alkaloid N-glucoside from the leaves of Panax vietnamensis Ha et Grushv. (Vietnamese ginseng).

Vietnamese ginseng (Panax vietnamensis Ha and Grushv., Araliaceae) is indigenous in the central highlands of Vietnam and the southernmost distribution in the Panax genus. Like other ginseng, Vietnamese ginseng is well known has been used as a tonic and for management of certain diseases in the traditional medicine. Nevertheless, it is noteworthy that in respect to the long history in use and systematic studied on Korean ginseng (P. ginseng), American ginseng (P. quinquefolius), Japanese ginseng (P. japonicus), and Chinese ginseng (P. notoginseng), the up-to-date published database on Vietnamese ginseng is relatively much less extensive. In our ongoing research on the promising Vietnamese medicinal plants, the present phytochemical investigation of the ethanol extract of the leaves of Panax vietnamensis led to the isolation of three compounds (1-3), including a new indole alkaloid N-glycoside (1) and two known compounds. Their structures were elucidated based on extensive physiochemical and chemical methods, especially the interpretation of NMR and MS spectra. The absolute configuration of 1 was determined based on the comparison of its experimental and theoretical ECD spectra along with NMR calculation. Compound 1 is naturally isolated N-glycoside, which is rarely found in natural products. The isolated compounds showed weak or no inhibitory activity against acetylcholinesterase enzyme (AChE).

Machine learning assisted interpretation of 2D solid-state nuclear magnetic resonance spectra

A machine learning methodology using deep neural network (DNN) for interpreting multidimensional solid-state nuclear magnetic resonance (SSNMR) of various synthetic and natural polymers is presented. The separated local field (SLF) SSNMR which correlates local well-defined heteronuclear dipolar with the tensor orientation of the chemical shift anisotropy (CSA) of spin in the solid state can provide valuable structure and molecular dynamics information of synthetic and biopolymers. Compared with the traditional linear least-square fitting, the proposed DNN-based methodology can efficiently and accurately determine the tensor orientation of CSA of both 13C and 15N in all four samples. The method achieves prediction precisions of the Euler angles with < ±5° and is characterized by low training costs and high efficiency (<1 s). The feasibility and robustness of the DNN-based analysis methodology are confirmed by comparison to reported-literature values. This strategy is expected to aid in the interpretation of complex multidimensional NMR spectra of complicated polymer system.

PH Effects Can Dominate Chemical Shift Perturbations in 1H,15N-HSQC NMR Spectroscopy for Studies of Small Molecule/α-Synuclein Interactions.

1H,15N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically disordered monomeric α-Synuclein (aSyn). We report how solution pH can impact the interpretation of aSyn HSQC NMR spectra and demonstrate that small-molecule formulations (e.g., complexation with acidic salts) can lower sample pH and confound interpretation of drug binding and concomitant protein structural changes. Through stringent pH control, we confirm that several previously identified compounds (EGCG, Baicalin, and Dopamine (DOPA)) as well as a series of potent small-molecule inhibitors of aSyn pathology (Demeclocycline, Ro90-7501, and (±)-Bay K 8644) are capable of direct target engagement of aSyn. Previously, DOPA-aSyn interactions have been shown to elicit a dramatic chemical shift perturbation (CSP) localized to aSyn's H50 at low DOPA concentrations then expanding to aSyn's acidic C-terminal residues at increasing DOPA levels. Interestingly, this CSP profile mirrors our pH titration, where a small reduction in pH affects H50 CSP, and large pH changes induce robust C-terminal CSP. In contrast, under tightly controlled pH 5.0, DOPA induces significant CSPs observed at both ionizable and nonionizable residues. These results suggest that previous interpretations of DOPA-aSyn interactions were conflated with pH-induced CSP, highlighting the need for stringent pH control to minimize potential false-positive interpretations of ligand interactions in HSQC NMR experiments. Furthermore, DOPA's preferential interaction with aSyn under acidic pH represents a novel understanding of DOPA-aSyn interactions that may provide insight into the potential gain of toxic function of aSyn misfolding in α-synucleinopathies.

Searching for the Best Values of NMR Shielding and Spin-Spin Coupling Parameters: CH4-nFn Series of Molecules as the Example.

Attempts at the theoretical interpretation of NMR spectra have a very long and fascinating history. Present quantum chemical calculations of shielding and indirect spin-spin couplings permit modeling NMR spectra when small, isolated molecules are studied. Similar data are also available from NMR experiments if investigations are performed in the gas phase. An interesting set of molecules is formed when a methane molecule is sequentially substituted by fluorine atoms-CH4-nFn, where n = 0, 1, 2, 3, or 4. The small molecules contain up to three magnetic nuclei, each with a one-half spin number. The spectral parameters of CH4-nFn can be easily observed in the gas phase and calculated with high accuracy using the most advanced ab initio methods of quantum chemistry. However, the presence of fluorine atoms makes the calculations of shielding and spin-spin coupling constants extremely demanding. Appropriate experimental 19F NMR parameters are good but also require some further improvements. Therefore, there is a real need for the comparison of existing NMR measurements with available state-of-the-art theoretical results for a better understanding of actual limits in the determination of the best shielding and spin-spin coupling values, and CH4-nFn molecules are used here as the exceptionally important case.

Flavonoid C-glucosides and monosaccharides from Combretum indicum

Introduction: Combretum indicum belongs to Combretaceae. This species was known to possess diverse bioactivities and chemical constituents. This paper reported the isolation and structural elucidation of five compounds from leaves of Combretum indicum collected in Ho Chi Minh City. Method: From the dried powder of Combretum indicum, the crude extract was obtained by maceration method in methanol at room temperature. Then this extract was separated into different extracts by absorbed on silica gel and eluted with different solvents. The organic compounds were then isolated by chromatography methods and were identified by MS and NMR spectra interpretation. Results: Five compounds comprising vitexin (1), orientin (2), isoorientin (3), D-glucose (4), and D-fructose (5) were isolated. Conclusion: To the best of our knowledge, all isolated compounds were reported from this species for the first time.

Effects of anion incorporation on the local structure of porous-type amorphous alumina prepared by anodization: NMR study of Al coordination numbers

Although anodization is an essential technology that has supported the aluminum industry for nearly a century, the atomistic structure of the formed alumina films has not completely understood. Here we used NMR spectroscopy to clarify the factors affecting local structure of anodic porous alumina films prepared under various electrolytic conditions. For anion-free amorphous alumina films prepared using chromic acid, the local structure does not depend on electrolytic factors. For films prepared using phosphoric acid, the average coordination number was lower than that of anion-free alumina. On the other hand, films prepared using oxalic and sulfuric acids showed the average coordination numbers higher than that of anion-free alumina. We reveal that aluminum coordination number of anodic porous alumina are affected by anion species and anion content. In addition, the depth of anion incorporation into cell walls, or compositional uniformity, is quite important for accurate interpretation of NMR spectra.

Reactivity of Perhalogenated Octahedral Phospha- and Arsaboranes toward THF: A Joint Experimental/Computational Study.

Reactions of the perhalogenated polyhedral pnictogenaboranes closo-1,2-Pn2B4Hal4 (Pn = P, As; Hal = Cl, Br) with Lewis bases are presently being studied with a focus on rationalizing the sites of nucleophilic attacks on clusters bearing σ-holes. These σ-holes are localized both on pnictogens and, for Hal = Br, on bromine atoms, as revealed by electrostatic potential (ESP) and intrinsic bond orbital (IBO) analyses. Surprisingly, the attack of the cyclic ether THF on closo-1,2-Pn2B4Br4 does not occur on the site with the largest positive partial charge, centered in the middle of the pnictogen-pnictogen vector. Instead, presumably promoted by the positivated bromine substituents, THF inserts into the boron-bromine bonds of the negatively charged boron atoms opposite to the pnictogen atoms to form 4-(4-bromobut-1-oxy)-closo-1,2-Pn2B4Br3 (1-PB and 1-AsB) and 4,6-(4-bromobut-1-oxy)2-closo-1,2-Pn2B4Br2 (2-PB and 2-AsB). 11B and 31P chemical shift computations at various levels support the assignments of the signals, which reflect the correctness of the molecular geometries in solutions. The Lewis-acidic perchlorinated analogues closo-1,2-P2B4Cl4, closo-1,2-As2B4Cl4, and the mixed closo-1,2-AsPB4Cl4 bear negative charges. These negative charges are revealed by the Vs,max values when computing the electrostatic potentials both on the boron and the chlorine atoms. Due to this negative charge, the analogues do not react with THF unless they are heated above 66 °C, where they slowly decompose to borate esters B(OR)3 without the formation of concrete intermediates. The evaluation of 31P NMR data of 1-PB has allowed the experimental determination of the coupling constant 1J(31P(1), 31P(2)) = |143| Hz in a closo-diphosphaborane for the first time, which agrees well with the computed value of -178 Hz. The pioneering joint experimental vs computational interpretation of 31P NMR spectra in the area of boron cluster chemistry was decisive for the structural characterization of 1-PB and 2-PB.

Synthesis and Tyrosinase Inhibitory Activity of (E)-5-Benzyl-7- (3-Bromobenzylidene)-3-(3-Bromophenyl)-2-Phenyl-3,3a, 4,5,6,7-Hexahydro-2H-Pyrazolo[4,3-c]Pyridine

The tyrosinase enzyme plays an essential role in the pigmentation of human skin, fruits, and vegetables. It has been tied with several human skin diseases and post-harvest problems. Hence, the tyrosinase enzyme becomes an excellent therapeutic target to overcome these issues. This study aimed to screen tyrosinase inhibitors by synthesizing halogen-substituted pyrazolopyridine derivatives. The pyrazolopyridine compound was obtained through two stages of synthesis. First, the intermediate compound, a derivative of 3,5-bis(arylidene)-4-piperidone, was synthesized through the Cleisen-Schmidt condensation reaction of 4-piperidone and benzaldehyde derivatives. Furthermore, the intermediate compound was reacted with phenylhydrazine through a cyclocondensation reaction to produce the titled compound with an 11% yield. The chemical structure of the target compound was identified through the interpretation of UV, FTIR, NMR, and HRMS spectra. Then an in vitro assay was conducted on the tyrosinase enzyme of the fungus Agaricus bisporus by detecting the presence of dopachrome at a wavelength of 492 nm. As a result, the in vitro assay showed that the titled compound had a weak inhibitory activity, and the IC50 value was &gt; 500 µM. Thus, the synthesized compound is considered inactive.

Spirovetivane- and Eudesmane-Type Sesquiterpenoids Isolated from the Culture Media of Two Cyanobacterial Strains.

As part of a study examining polar metabolites produced by cyanobacterial strains, we examined media extracts of a Calothrix sp. (strain R-3-1) and a Scytonema sp. (strain U-3-3). The cell mass of each was separated from the media, and HP20 resin was added for adsorption of secreted metabolites, a relatively unexplored area of cyanobacterial chemistry. HPLC-UV-LCMS-guided isolation led to the discovery of seven sesquiterpenoid compounds with five new, one known, and one previously isolated as the methyl ester. Through a complement of 1D and 2D NMR spectroscopic techniques, the planar structures and relative configurations of the seven compounds were elucidated. Spironostoic acid (1), 11,12-didehydrospironostoic acid (2), and 12-hydroxy-2-oxo-11-epi-hinesol (4) are spirovetivane-type compounds from R-3-1, while stigolone (5), 11R,12-dihydroxystigolone (6), and 11S,12-dihydroxystigolone (7) are three eudesmane-type compounds from U-3-3. Circular dichroism was utilized to decipher the absolute configurations of new compounds 1, 2, 4, 5, 6, and 7. Due to the structural variety observed among the spirovetivane- and eudesmane-type compounds in the literature and often a lack of clarity in how determinations were made, computational spectra and model compounds were used to support the interpretation of ECD and NMR spectra. A straightforward process to determine the configuration of these systems is presented.

The chemical constituents of the n-hexane extract of Marchantia polymorpha L.

Introduction: Marchantia polymorpha belongs to the liverwort family. Marchantia species are known to possess diverse chemical constituents and bioactivities. As part of a chemically systematic study of liverworts, the isolation and structural elucidation of six compounds from Marchantia polymorpha were reported. Method: A dried powder of Marchantia polymorpha was macerated in methanol to prepare the crude extract. Then, the liquid–liquid partition method was applied to this extract to separate it into different polar extracts, including n-hexane, ethyl acetate extracts, and residue. The Sephadex LH-20 and silica gel column chromatography and recrystallization methods were used to isolate organic compounds. Their chemical structures were determined by usual techniques such as MS and NMR spectra interpretation in comparison with the experimentally spectroscopic data reported. Results: Six compounds consisting of marchantin G (1), quercetin (2), kaempferol (3), hexaconazole (4), indole-3-carboxylic acid (5), and sitosterol 3-O-β-D-glucopyranoside (6) were isolated. Conclusion: To the best of our knowledge, although all isolated compounds were known to be present in other species, they were reported from this species for the first time.

Mansouramycins E-G, Cytotoxic Isoquinolinequinones from Marine Streptomycetes.

Chemical investigation of the ethyl acetate extract from the marine-derived Streptomyces sp. isolate B1848 resulted in three new isoquinolinequinone derivatives, the mansouramycins E–G (1a–3a), in addition to the previously reported mansouramycins A (5) and D (6). Their structures were elucidated by computer-assisted interpretation of 1D and 2D NMR spectra, high-resolution mass spectrometry, and by comparison with related compounds. Cytotoxicity profiling of the mansouramycins in a panel of up to 36 tumor cell lines indicated a significant cytotoxicity and good tumor selectivity for mansouramycin F (2a), while the activity profile of E (1a) was less attractive.

Synthesis of a Biodegradable PLA: NMR Signal Deconvolution and End-Group Analysis

NMR spectroscopy is a powerful spectroscopic tool that not only allows the determination of structures after synthesis, as usually explained to students of Organic Chemistry, but also is useful in many other fields such as medicine imaging, real-time industrial processes, material sciences, or metabolomics. In this experiment, students performed a ring-opening polymerization (ROP) reaction in the laboratory and, then, collected a series of 1D NMR spectra with the aim of determining the tacticity of the polymers formed and their number-average molecular weight. The deconvolution of 1H and 13C NMR experimental data was central in their learning process, and the consistence of the results obtained was validated within the literature. This exercise gave students skills on polymerization reaction processes, instrumental analysis, and determination and interpretation of NMR spectra in the use of deconvolution procedures along with the critical evaluation of the obtained results.

What Is Being Measured with P-Bearing NMR Probe Molecules Adsorbed on Zeolites?

Elucidating the nature, strength, and siting of acid sites in zeolites is fundamental to fathom their reactivity and catalytic behavior. Despite decades of research, this endeavor remains a major challenge. Trimethylphosphine oxide (TMPO) has been proposed as a reliable probe molecule to study the acid properties of solid acid catalysts, allowing the identification of distinct Brønsted and Lewis acid sites and the assessment of Brønsted acid strengths. Recently, doubts have been raised regarding the assignment of the 31P NMR resonances of TMPO-loaded zeolites. Here, it is shown that a judicious control of TMPO loading combined with two-dimensional 1H-31P HETCOR solid-state NMR, DFT, and ab initio molecular dynamics (AIMD)-based computational modeling provides an unprecedented atomistic description of the host-guest and guest-guest interactions of TMPO molecules confined within HZSM-5 molecular-sized voids. 31P NMR resonances usually assigned to TMPO molecules interacting with Brønsted sites of different acid strength arise instead from both changes in the probe molecule confinement effects at ZSM-5 channel system and the formation of protonated TMPO dimers. Moreover, DFT/AIMD shows that the 1H and 31P NMR chemical shifts strongly depend on the siting of the framework aluminum atoms. This work overhauls the current interpretation of NMR spectra, raising important concerns about the widely accepted use of probe molecules for studying acid sites in zeolites.

One-Pot Synthetic Approach to Dipyrromethanes and Bis(indolyl)methanes via Nitrosoalkene Chemistry

A one-pot regio- and stereoselective synthesis of a dipyrromethane and a bis(indolyl)methane based on two consecutive reactions of nitrosoalkenes with pyrrole or indole, respectively, is described as an experiment to be carried out by upper-division undergraduate students in a laboratory classroom. Importantly, the ability of electrophilic conjugated nitrosoalkenes to react via Michael addition or hetero-Diels–Alder reactions with electron-rich heterocycles will provide an opportunity for students to acknowledge alternative reaction pathways underlying certain transformations. Reactions were performed under mild conditions using water as a solvent, followed by purification through column chromatography on silica gel, and characterization of the desired products by NMR and IR spectroscopy. This laboratory experiment combines organic synthesis, determination of the purity of compounds (TLC analysis and melting point measurements), as well as structural analysis (interpretation of 1D NMR spectra). Several important organic chemistry concepts, such as stereo- and regioselectivity, in situ generation and reactivity of conjugated nitrosoalkenes, conjugated 1,4-addition reactions, and cycloaddition reactions, are also discussed.