NMR Chemical Shift Calculations Research Articles

An Actinide Complex with a Nucleophilic Allenylidene Ligand.

The reaction of [Cp3Th(3,3-diphenylcyclopropenyl)] (Cp = η5-C5H5) with 1 equiv of lithium diisopropylamide (LDA) results in cyclopropenyl ring opening and formation of the thorium allenylidene complex, [Li(Et2O)2][Cp3Th(CCCPh2)] ([Li(Et2O)2][1]), in good yield. Additionally, deprotonation of [Cp3Th(3,3-diphenylcyclopropenyl)] with 1 equiv of LDA, in the presence of 12-crown-4 or 2.2.2-cryptand, results in the formation of discrete cation/anion pairs, [Li(12-crown-4)(THF)][Cp3Th(CCCPh2)] ([Li(12-crown-4)(THF)][1]) and [Li(2.2.2-cryptand)][Cp3Th(CCCPh2)] ([Li(2.2.2-cryptand)][1]), respectively. Interestingly, the complex [Li(Et2O)2][1] undergoes dimerization upon standing at room temperature, resulting in the formation of [Cp2Th(μ:η1:η3-CCCPh2)]2 (2), via loss of LiCp. The reaction of [Li(Et2O)2][1] with MeI results in electrophilic attack at the Cγ carbon atom, leading to the formation of a thorium acetylide complex, [Cp3Th(C≡CC(Me)Ph2)] (3), which can be isolated in 83% yield upon workup, whereas the reaction of [Li(Et2O)2][1] with benzophenone results in the formation of 1,1,4,4-tetraphenylbutatriene (4) in 99% yield, according to integration against an internal standard. Density functional theory (DFT) calculations performed on [1]- and 2 reveal significant electron delocalization across the allenylidene ligand. Additionally, calculations of the 13C NMR chemical shifts for the Cα, Cβ, and Cγ nuclei of the allenylidene ligand were in good agreement with the experimental shifts. The calculations reveal modest deshielding induced by spin-orbital effects originating at Th due to the involvement of the 5f orbitals in the Th-C bonds. According to a DFT analysis, the cyclopropenyl ring-opening reaction proceeds via [Cp3Th(η1-3,3-Ph2-cyclo-C3)]- (IM), which features a carbanion character at Cβ.

Ether-Diol Ambiguity: An Inconspicuous Issue in the Structure Elucidation of Oxygenated Natural Products.

Tertiary and allylic hydroxyl groups readily eliminate water during positive ion mode mass spectrometry and may show similar NMR spectra to their corresponding ethers. In a routine structure elucidation workflow, these factors can cause researchers to incorrectly assign diol moieties as ethers or vice versa, leading to inaccurate chemical structures. After facing this problem during our work on oxygenated sesquiterpenoids from a Fusarium sp. fungal strain, we became aware of this challenging issue. We examined the literature for oxygenated natural products bearing these functional groups, and with the aid of density functional calculations of NMR chemical shifts, we now report the structures of 15 natural products that should be revised. We further establish that derivatizing sub-micromolar amounts of alcohols to their sulfates can be used to distinguish these from their corresponding ethers using liquid chromatography negative ion mode mass spectrometry. Finally, we isolated lignoren/cyclonerodiol from the Fusarium sp. culture extract and supported its revised identity as cyclonerodiol using this sulfation approach. Our results suggest that ether-diol ambiguity could be a prevalent issue affecting the structure elucidation of oxygenated natural products and highlight the importance of using complementary techniques, such as sulfation with LC-(-)-ESI-MS or density functional calculations of NMR chemical shifts.

Synthesis, structural analysis, and molecular docking of a novel 1,3,4-thiadiazole derivative: An experimental and molecular modeling studies

This study reports on the synthesis and characterization of a new thiadiazole derivative, (E)-N-(5-(2-nitrostyryl) -4-acetyl -4,5-dihydro -1,3,4-thiadiazol -2-yl) -N-phenylacetamide (ETDZ). The crystal structure was determined by single-crystal X-ray diffraction. ETDZ belongs to the monoclinic I2/a space group. The contribution of intermolecular interactions was assessed by Hirshfeld surface analysis and fingerprint plots. FT-IR, UV–Vis, and NMR (1H and 13C) techniques were used for spectroscopic characterization. The 1H and 13C NMR spectra were recorded in CDCl3 solvent. Density functional theory, employing the B3LYP functional and 6–311G(d,p) basis set in chloroform solvent, was used to calculate the structural and spectroscopic parameters of the molecule in the ground state. The vibrational wavenumbers were calculated and compared with the experimental FT-IR spectrum using the scaled quantum mechanics method. Isotropic chemical shifts were calculated using the Gauge invariant atomic orbital method. The calculated NMR chemical shifts and absorption wavelengths were compared with the experimental values, indicating good results from the DFT and TD-DFT methods. To get more information about charge transfer within the molecule, electronic properties such as HOMO and LUMO energies were studied using the DFT approach. The molecular electrostatic potential, frontier molecular orbital analysis, energy band gap, density of state, global chemical reactivity descriptors, and some thermodynamic functions were also calculated. Reduced density gradient and atom-in-molecule analysis were performed to investigate inter- and intra-non-covalent interactions. Molecular docking was carried out with the Eg5 kinesin protein, confirming the biological assets of the ETDZ ligand as a mitochondria disease and cancer agent.

Comprehensive study on pyrano[3,2-c]quinoline-based indole: Synthesis, characterization, and potential for optoelectronic and photovoltaic applications

The target indolylidenehydrazinylidenemethyl-pyrano[3,2-c]quinoline (IHMPQ) was synthesized and characterized. The DFT/ B3LYP approach using the 6–311++G(d,p) basis set was used to carry out the quantum computational calculations. The energy values of certain quantum chemical properties were calculated. The molecular electrostatic potential (MEP) and non-linear optical (NLO) characteristics are investigated. The Fukui function was used to forecast the reactive sites for electrophilic and nucleophilic attack using Mulliken population analysis. The calculated NMR chemical shifts were compared to experimental results. Furthermore, the study assessed the drug-likeness of the current compounds and discovered that they adhered to Lipinski's rule of five, making them appropriate for the development of oral drugs. Scanning electron microscopy was used to analyze the topography of the IHMPQ structure. The experimental results revealed a direct allowed energy gap, with values of 2.01 eV and 3.3 eV. Notably, IHMPQ films exhibit remarkable photoluminescence and absorption properties, suggesting their suitability for optoelectronic applications. Moreover, the investigation into the J-V characteristics of IHMPQ film-based devices under diverse illuminations unveiled a distinct response to incident light. This suggests the potential utility of these devices in solar cell applications.

Formation of hydrogen bonding network of methane sulfonic acid at low degree of hydration (MSA)m·(H2O)n (m = 1–2 and n = 1–5)

This study employs ab initio calculations based on density functional theory (DFT) to investigate the structural properties, 1H-NMR spectra, and vibrational spectra of methane sulfonic acid (MSA) at low degree of hydration. The findings reveal that energetically stable structures are formed by small clusters consisting of one or two MSA molecules (m = 1 and 2) and one or two water molecules in (MSA)m·(H2O)n (m = 1–2 and n = 1–5).These stable structures arise from the formation of strong cyclic hydrogen bonds between the proton of the hydroxyl (OH) group in MSA and the water molecules. However, clusters containing three or more water molecules (n > 2) exhibit proton transfer from MSA to water, resulting in the formation of ion-pairs composed of CH3SO3− and H3O+species. The measured 1H-NMR spectra demonstrate the presence of hydrogen-bonded interactions between MSA and water, with a single MSA molecule interacting with water molecules. This interaction model accurately represents the hydrogen bonding network, as supported by the agreement between the experimental and calculated NMR chemical shift results.

A new resorcylic acid lactone from the endophytic fungus Chaetosphaeronema sp.

A new 14-membered resorcylic acid lactone (RAL14), chaetolactone A (1), along with three known ones (2−4), was obtained from the fermentation of the soil-derived fungus Chaetosphaeronema sp. SSJZ001. Their structures were established based on extensive spectroscopic data analyses (UV, IR, HRESIMS, 1D, and 2D NMR),13C NMR chemical shifts calculations coupled with the DP4+ probability method, theoretical calculations of ECD spectra, as well as X-ray diffraction analysis. All compounds were evaluated for their cytotoxic effects against A549, HO-8910, and MCF-7 cell lines.

Retinestatin, a Polyol Polyketide from a Termite Nest-Derived Streptomyces sp.

A new polyol polyketide, named retinestatin (1), was obtained and characterized from the culture of a Streptomyces strain, which was isolated from a subterranean nest of the termite Reticulitermes speratus kyushuensis Morimoto. The planar structure of 1 was elucidated on the basis of the cumulative analysis of ultraviolet, infrared, mass spectrometry, and nuclear magnetic resonance spectroscopic data. The absolute configuration of 1 at 12 chiral centers was successfully assigned by employing a J-based configuration analysis in combination with ROESY correlations, a quantum mechanics-based computational approach to calculate NMR chemical shifts, and a 3 min flash esterification by Mosher's reagents followed by NMR analysis. Biological evaluation of retinestatin (1) using an in vitro model of Parkinson's disease revealed that 1 protected SH-SY5Y dopaminergic cells from MPP+-induced cytotoxicity, indicating its neuroprotective effects.

Siamfuranones A–C, three novel furanone derivatives from the flowers of Uvaria siamensis and their biological activities

Three previously undescribed furanone derivatives named siamfuranones A–C (1–3), together with 11 known compounds (4–14), were isolated from the flowers of Uvaria siamensis. Their planar structures were determined through analysis of spectrometric and spectroscopic evidence, while electronic circular dichroism (ECD) calculations were used to determine their absolute configurations. In addition, gauge-including atomic orbitals (GIAO) NMR chemical shift calculation, supported by the advanced statistical method DP4 plus, was used to confirm the relative configuration of siamfuranone B (2). All the isolated compounds were evaluated against two cancer cell lines (A549 and Hela), and screened for antibacterial activities. Furthermore, they were assessed for cytotoxicity against a normal cell line (Vero cell).

Kagimminols A and B, Cembrene-Type Diterpenes from an Okeania sp. Marine Cyanobacterium.

Kagimminols A (1) and B (2), new cembrene-type diterpenoids, were isolated from an Okeania sp. marine cyanobacterium. By combining DP4 analysis with an efficient NMR chemical shift calculation protocol, we clarified the relative configurations of 1 and 2 without consuming precious natural products. We determined the absolute configurations by a comparison of theoretical electronic circular dichroism (ECD) spectra with experimental spectra, and the absolute configuration of 1 was verified experimentally. Finally, we found that 1 and 2 showed selective growth-inhibitory activity against the causative agent of human African trypanosomiasis. This study exemplifies that computational chemistry is an efficient tool for clarifying the configurations of natural products possessing tautomers in equilibrium.

Discovery of P450-Modified Sesquiterpenoids Levinoids A-D through Global Genome Mining.

Cytochrome P450-modified bacterial terpenoids remain in a vast chemical space to be explored. In the present study, we conducted global genome mining of 223,829 bacterial genomes and identified 2892 bacterial terpenoid biosynthetic gene clusters (BGCs) with cytochrome P450 genes. Among these, we selected 562 with multiple P450 enzymes, which were further clustered as 355 gene cluster families by sequence similarity analysis. We then chose lev, a BGC from Streptomyces levis MCCC1A01616, for heterologous expression and discovered four new α-amorphene-type sesquiterpenoids, levinoids A-D (1-4). The structures and absolute configurations of these four new compounds were determined by employing extensive NMR analysis, NMR chemical shift calculations with DP4+, and ECD calculations. Furthermore, levinoid C (3) exhibited a moderate level of neuroprotective activity (EC50 = 21 μM) in the glutamate-induced excitotoxicity cell model. Our findings highlight the untapped chemical diversity of P450-modified bacterial terpenoids, opening new avenues for further exploration and discovery.

Phenolics and terpenoids with good anti-inflammatory activity from the fruits of Amomum villosum and the anti-inflammatory mechanism of active diterpene

The fruits of Amomum villosum are often considered a medicinal and food homologous material and have been found to have therapeutic effects in chronic enteritis, gastroenteritis, and duodenal ulcer. The aim of this study is to discover the anti-inflammatory active ingredients from dried ripe fruits of A. villosum and to elucidate the molecular mechanisms. We verified that the inhibitory activity of the ethyl acetate extract was superior to Dexamethasone (Dex), so we ultimately chose to study the ethyl acetate extract from the fruits of A. villosum. A total of 33 compounds were isolated from its ethyl acetate extract, including nine known diterpenoids (compounds 1–9), twelve known sesquiterpenoids (compounds 10–21), ten known phenolics (compounds 22, 23, 25–29, 31–33) and two new phenolics (24 and 30). On the basis of chemical evidences and spectral data analysis (UV, ECD, Optical rotation data, 1D and 2D-NMR, HR-ESI-MS, NMR chemical shift calculations), the structures of new compounds were elucidated. Among these compounds, isocoronarin D (5) was found to have good anti-inflammatory activity. Further research has found that isocoronarin D can down-regulate the protein levels of COX2 and NOS2, activate Nrf2/Keap1 and suppress NF-κB signaling pathway in LPS-induced RAW264.7 cells. In addition, isocoronarin D inhibited inflammasome assembly during inflammasome activation by hampering the binding of NLRP3 and ASC. Further evidence revealed that isocoronarin D suppressed the assembly of the NLRP3 inflammasome via blocking the formation of ASC specks. From these results, isocoronarin D may be the important bioactive compound of A. villosum and exhibits anti-inflammatory effects by regulating the NF-κB/Nrf2/NLRP3 axis in macrophages.

The Scope of the Applicability of Non-relativistic DFT Calculations of NMR Chemical Shifts in Pyridine-Metal Complexes for Applied Applications.

Heavy metals are toxic, but it is impossible to stop using them. Considering the variety of molecular systems in which they can be present, the multicomponent nature and disorder of the structure of such systems, one of the most effective methods for studying them is NMR spectroscopy. This determines the need to calculate NMR chemical shifts for expected model systems. For elements beyond the third row of the periodic table, corrections for relativistic effects are necessary when calculating NMR parameters. Such corrections may be necessary even for light atoms due to the shielding effect of a neighboring heavy atom. This work examines the extent to which non-relativistic DFT calculations are able to reproduce experimental 15N and 113Cd NMR chemical shift tensors in pyridine-metal coordination complexes. It is shown that while for the calculation of 15N NMR chemical shift tensors there is no real need to consider relativistic corrections, for 113Cd, on the contrary, none of the tested calculation methods could reproduce the experimentally obtained tensor to any extent correctly.

Antiproliferative polyketides from fungus Xylaria cf. Longipes SWUF08-81 in different culture media

Bioactive compounds from the wood-decay fungus Xylaria cf. longipes SWUF08-81, cultivated in three different culture media (GM, YM and PDB), were isolated. Their structures and stereochemistry were deduced from spectroscopic and MS data analysis, together with quantum chemical calculations of 13C NMR chemical shifts and electronic circular dichroism (ECD) spectra. Five undescribed polyketides including dibenzofuran (1), mellein (2), dihydroisocoumarin (15), and two pyrans (16, 17), together with twenty-three compounds were determined. Compounds 18 and 20 were significantly toxic against cancer cell lines (HCT116, HT29, MCF-7 and HeLa) based on the MTT assay. Quantification by HPLC showed that 18 was produced three-fold higher in the broth of PDB than YM. These studies showed that the production of different compounds were primarily dependent on nutrition sources and it has given a starting point for the growth optimization conditions for the scaling up of bioactive compounds production.Graphical

Stereochemical and NMR computational study of some natural dimeric bisindole alkaloids

AbstractThe initial conformational search followed by the optimization of geometric parameters and high‐level calculation of 1H and 13C NMR chemical shifts were carried out for 12 bisindole alkaloids of the Corynanthe‐Strychnos series. Configurational assignments of all compounds from this series were performed based on the correlation of calculated and experimental NMR chemical shifts. For some alkaloids, the reassignment of the individual resonances together with spectral assignment of experimentally unresolved signals were suggested.

New fusidane-type nortriterpenoids from the Arctic marine-derived fungus Simplicillium lamellicola culture medium with their inhibitory effect on benign prostatic hyperplasia

Three new fusidane-type nortriterpenoids, simplifusinolide A, 24-epi simplifusinolide A, and simplifusidic acid L (1–3), were isolated from the EtOAc extract of the Arctic marine-derived fungus Simplicillium lamellicola culture medium, together with fusidic acid (4) and 16-O-deacetylfusicid acid (5). The structures of the isolated compounds were elucidated by NMR and MS analyses. The absolute configurations of compounds 1–3 were established by the quantum mechanical calculations of electronic circular dichroism and gauge-including atomic orbital NMR chemical shifts, followed by DP4 + analysis.Benign prostatic hyperplasia (BPH) is a major urological disorder in men worldwide. The anti-BPH potentials of the isolated compounds were evaluated using BPH-1 and WPMY-1 cells. Treatment with simplifusidic acid L (3) and fusidic acid (4) significantly downregulated the mRNA levels of the androgen receptor (AR) and its downstream effectors, inhibiting the proliferation of BPH-1 cells. Specifically, treatment with 24-epi simplifusinolide A (2) significantly suppressed the cell proliferation of both BPH-1 and DHT-stimulated WPMY-1 cells by inhibiting AR signaling. These results suggest the potential of 24-epi simplifusinolide A (2), simplifusidic acid L (3) and fusidic acid (4) as alternative agents for BPH treatment by targeting AR signaling.

Machine learning-based correction for spin-orbit coupling effects in NMR chemical shift calculations.

As one of the most powerful analytical methods for molecular and solid-state structure elucidation, NMR spectroscopy is an integral part of chemical laboratories associated with a great research interest in its computational simulation. Particularly when heavy atoms are present, a relativistic treatment is essential in the calculations as these influence also the nearby light atoms. In this work, we present a Δ-machine learning method that approximates the contribution to 13C and 1H NMR chemical shifts that stems from spin-orbit (SO) coupling effects. It is built on computed reference data at the spin-orbit zeroth-order regular approximation (ZORA) DFT level for a set of 6388 structures with 38 740 13C and 64 436 1H NMR chemical shifts. The scope of the methods covers the 17 most important heavy p-block elements that exhibit heavy atom on the light atom (HALA) effects to covalently bound carbon or hydrogen atoms. Evaluated on the test data set, the approach is able to recover roughly 85% of the SO contribution for 13C and 70% for 1H from a scalar-relativistic PBE0/ZORA-def2-TZVP calculation at virtually no extra computational costs. Moreover, the method is transferable to other baseline DFT methods even without retraining the model and performs well for realistic organotin and -lead compounds. Finally, we show that using a combination of the new approach with our previous Δ-ML method for correlation contributions to NMR chemical shifts, the mean absolute NMR shift deviations from non-relativistic DFT calculations to experimental values can be halved.

Study of the Three-Dimensional Structure of Tryptophan Zipper Peptides through 1H NMR Chemical Shifts Calculations

Three-dimensional structures of proteins are intimately linked to their functions, therefore understanding their conformation in solution is essential. While nuclear magnetic resonance spectroscopy and X-ray crystallography are widely employed for protein structural determination, their limitations make the process challenging and expensive. Theoretical calculations of chemical shifts present a potential complement to experimental techniques, facilitating the study of protein structures. This investigation aims to assess the applicability of chemical shift calculations in analyzing three-dimensional structures of peptides, focusing on the tryptophan zipper 1 peptide as a model. Furthermore, a mutated variant of this peptide was proposed to evaluate the stability of its structural elements under sequence modifications. Through calculations, a potential structural alteration in the β-turn region of the mutant peptide compared to tryptophan zipper 1 was identified. This research demonstrates the potential of using computational approaches to complement experimental methods in studying protein structures and their functional implications.

The accuracy limit of chemical shift predictions for species in aqueous solution.

Interpreting NMR experiments benefits from first-principles predictions of chemical shifts. Reaching the accuracy limit of theory is relevant for unambiguous structural analysis and dissecting theoretical approximations. Since accurate chemical shift measurements are based on using internal reference compounds such as trimethylsilylpropanesulfonate (DSS), a detailed comparison of experimental with theoretical data requires simultaneous consideration of both target and reference species ensembles in the same solvent environment. Here we show that ab initio molecular dynamics simulations to generate liquid-state ensembles of target and reference compounds, including explicitly their short-range solvation environments and combined with quantum-mechanical solvation models, allows for predicting highly accurate 1H (∼0.1-0.5 ppm) and aliphatic 13C (∼1.5 ppm) chemical shifts for aqueous solutions of the model compounds trimethylamine N-oxide (TMAO) and N-methylacetamide (NMA), referenced to DSS without any system-specific adjustments. This encompasses the two peptide bond conformations of NMA identified by NMR. The results are used to derive a general-purpose guideline set for predictive NMR chemical shift calculations of NMA in the liquid state and to identify artifacts of force field models. Accurate predictions are only obtained if a sufficient number of explicit water molecules is included in the quantum-mechanical calculations, disproving a purely electrostatic model of the solvent effect on chemical shifts.

Impacts of basis sets, solvent models, and NMR methods on the accuracy of 1H and 13C chemical shift calculations for biaryls: a DFT study

Introduction: Biaryls are core structures composed of chiral ligands, organocatalysts, biologically active natural products and biopolymer lignins. In this study, the effects of basis sets, solvent models, and NMR methods on the accuracy of 1H/13C NMR chemical shift calculations for biaryl structures were evaluated. Methods: All calculations were performed using Gaussian09. The GIAO NMR results were observed and extracted using GaussView05. To reduce the systematic error of the calculations, linear regression analysis of the calculated chemical shifts versus the experimental shifts was performed. Results: The tested basis sets showed good 1H/13C results, with CMAE values as low as 0.0425 ppm and 1.09 ppm for 1H and 13C, respectively. The use of solvent models significantly increased the accuracy of the 1H chemical shift calculations. The GIAO method produced more accurate results than did the IGAIM and CSGT methods. Conclusion: This study recommends 6-31G(d,p) and DGDZVP basis sets, IEMPCM and CPCM solvent models, and GIAO NMR methods for the accurate prediction of 1H and 13C chemical shifts for biaryls, assisting in their full structural assignments.

Pinuseldarone, a Clerodane-Type Diterpene from Pinus eldarica Needles and Phytochemicals as Novel Agents for Regulating Brown Adipogenesis and Thermogenesis.

Phytochemical investigation of the MeOH extract of Pinus eldarica needles led to the isolation and identification of a new clerodane-type diterpene, pinuseldarone (1), along with a known flavonoid, 5,4'-dihydroxy-3,7,8-trimethoxy-6-C-methylflavone (2), through HPLC purification. The structure of the new compound 1 was elucidated using spectroscopic methods, including 1D and 2D NMR, as well as HRESIMS. Its absolute configuration was established through NOESY analysis and computational methods, including electronic circular dichroism (ECD) calculations and gauge-including atomic orbital NMR chemical shift calculations, followed by DP4+ probability analysis. The metabolic implications of the isolated compounds were assessed using a cultured brown adipocyte model derived from murine brown adipose tissue. It was observed that treatment with dihydroxy-3,7,8-trimethoxy-6-C-methylflavone (2) downregulates the adipogenic marker C/EBPδ and fatty acid transporter CD36, resulting in a significant reduction in lipid accumulation during brown adipocyte differentiation. However, pinuseldarone (1) treatment did not affect brown adipocyte differentiation. Interestingly, pretreatment with pinuseldarone (1) potentiated the pharmacological stimulation of brown adipocytes, seemingly achieved by sensitizing their response to β3-adrenoreceptor signaling. Therefore, our findings indicate that phytochemicals derived from P. eldarica needles could potentially serve as valuable compounds for adjusting the metabolic activity of brown adipose tissue, a vital component in maintaining whole-body metabolic homeostasis.