NMR Chemical Shift Calculations Research Articles

NMR Calculations with Quantum Methods: Development of New Tools for Structural Elucidation and Beyond.

Structural elucidation is an important and challenging stage in the discovery of new organic molecules. Single-crystal X-ray analysis provides the most unquestionable results, though in practice the availability of suitable crystals limits its broad use. On the other hand, NMR spectroscopy has become the leading and universal technique to accomplish the task. Despite continuous advances in the field, the misinterpretation of NMR data is commonplace, evidenced by the large number of erroneous structures being published in top journals. Quantum calculations of NMR chemical shifts and scalar coupling constants emerged as ideal complements to facilitate the elucidation process when experimental NMR data is inconclusive. Since seminal reports demonstrated that affordable DFT methods provide NMR predictions accurate enough to differentiate among closely related isomers, the discipline has experienced substantial growth. The impact has been felt in different areas, and nowadays the results of such calculations are routinely seen in high impact literature.This Account describes our investigations in the field of quantum NMR calculations, focusing on the development of tools for structural elucidation and practical applications. We pioneered the use of artificial intelligence methods in the development of novel strategies of structural validation. Our first generation of trained artificial neural networks (ANNs) showed excellent ability to identify mistakes at the atom connectivity level, whereas the use of multidimensional pattern recognition pushed the performance to the stereochemical limit. In a conceptually different approach, we developed DP4+, an updated version of the DP4 probability used to determine the most likely structure among two or more candidates when one set of experimental data is available. Increasing the level of theory in NMR calculations and including unscaled data in the formalism improved the performance of the method, further validated to settle the configuration of challenging motifs such as spiroepoxides or Mosher's derivatives. One of the limitations of DP4+ is related to the relatively large computational cost involved in obtaining DFT-optimized geometries, which led to the development of a fast variant including the valuable information provided by coupling constants (J-DP4 method).These tools were explored to suggest the most probable structure of controversial natural or unnatural products originally misassigned, with some predictions further validated by synthesis (as in the case of pseudorubriflordilactone B). The possibility of predicting the structure of a natural product without requiring authentic sample was investigated in collaboration with Prof. Pilli (UNICAMP, Brazil) in the computer-guided total synthesis and stereochemical revisions of several natural products. Despite these advances, there remain considerable challenges, such as the case of configurational assessment of polar systems featuring multiple intramolecular hydrogen bonding interactions because of the poor energy predictions provided by most DFT methods. In our latest work, we tackle this problem by averaging the results provided by randomly generated ensembles, paving the way for a new paradigm in quantum NMR-assisted structural elucidation.

Design, Construction, and Characterization of a New Regioisomer and Diastereomer Material Based on the Spirooxindole Scaffold Incorporating a Sulphone Function

The 1,3-dipolar cycloaddition reaction is one of the most rapid, and efficient protocols to access, and construct highly divergent heterocycle chiral auxiliaries. Free catalyst synthesis of spirooxindole scaffold incorporating sulphone moiety via one pot–three component reaction of 6-chloro-isatin, L-proline, and the phenylvinylsulphone as dienophile is presented. The new regioisomer and diastereomer was isolated by precipitation without the tedious purification step, and then characterized via NMR and single crystal X-ray diffraction analysis. Using Hirshfeld analysis, the analysis of molecular packing was performed. It depended mainly on strong O…H and N…H interactions, and weak H…H, C…H, and Cl…H interactions as well. DFT calculations were used to optimize the experimental X-ray structure, which was found well matched with the calculated one. Reactivity descriptors based on the energies of the highest occupied (HOMO) and lowest unoccupied (LUMO) molecular orbitals were calculated. Additionally, the donor–acceptor interactions which stabilized the system via σ–σ*, π→π*, n→σ* and n→π* electron delocalization processes were also computed using NBO calculations. The net interaction energies are 49.96, 235.38, 179.66 and 107.06 kJ/mol, respectively. Additionally, the calculated NMR chemical shifts correlated well with the experimental data (R2=0.99).

Homochiral imidazolium-based dicarboxylate compounds: Structure and solution behaviour

Treatment of (S,S)- and (R,R)-1-(1-carboxy-2-methylpropyl)-3-(1-carboxylate-2-methylpropyl)imidazolium compounds, (S,S)-HLiPr and (R,R)-HLiPr, with the appropriate base yielded sodium, ammonium and lithium salts of the corresponding chiral anion in good yields. Compounds {Na[(S,S)-LiPr]}n (1s), {Na[(R,R)-LiPr]}n (1r), {NH4[(S,S)-LiPr]}n (2s), {NH4[(R,R)-LiPr]}n (2r), {Li[(S,S)-LiPr]}n (3s) and {Li[(R,R)-LiPr]}n (3r) were characterised by analytical and spectroscopic (IR, 1H and 13C NMR and polarimetry) methods. Specifically, 1r-3r are the first examples of homochiral compounds containing imidazolium-dicarboxylate ligands that were prepared from non-proteinogenic amino acids. In solution, NMR showed dissociation and this fact was confirmed by the good agreement found between the experimental and calculated NMR chemical shifts of the [LiPr]− anion. Interestingly, a transient carbene intermediate was proposed by DFT calculations in order to explain the solution H-D exchange observed by NMR at the C2-H atom of imidazolium ring. These compounds were also characterised by single-crystal (1s,r and 2s,r) or powder diffraction methods (3s). At the solid state, they are novel one-dimensional coordination polymers in which cations are connected via chiral 2,2′-(imidazolium-1,3-diyl)bis(3-methylbutanoate) anion. For this anion, unprecedented μ4-κ2O1, κ2O3, κ1O4 coordination mode was observed in 1s.

Decumbic anhydride from the stem barks of Swintonia floribunda (Anacardiaceae).

From an EtOAc-soluble fraction of the stem barks of Swintonia floribunda (Anacardiaceae), decumbic anhydride (1) and four known compounds 2-5 were isolated. Their chemical structures were elucidated based on the spectroscopic data interpretation. The GIAO-DFT calculation of 13C NMR chemical shifts was carried out to clarify the structure of 1. The absolute configuration of 1 was assigned based on the Cotton effects in its ECD spectrum. Compound 1 showed potent tyrosinase inhibitory activity with an IC50 value of 52.2μM.

Antifungal Phenols from Woodfordia uniflora Collected in Oman.

Woodfordia uniflora is a flowering shrub unique to the Dhofar region of Oman and is used locally as a sedative and remedy for skin infection. However, no study to date has examined the pharmacological properties of this plant, and studies regarding phytochemicals present in W. uniflora are limited. Herein, phytochemical screening of the extract of W. uniflora was performed using LC/MS. Three new phenolic compounds, (±)-woodfordiamycin (1), woodfordic acid (2), and rhamnetin 3-O-(6″-galloyl)-β-d-glucopyranoside (3), together with 16 known compounds 4-19, were isolated from the antifungal fraction of the extract. The structures of the new compounds were established by NMR and HR-MS data, and their absolute configurations were established using chemical transformations, including Mosher's method, comparison of experimental and calculated electronic circular dichroism data, and gauge-including atomic orbital NMR chemical shift calculations, followed by DP4+ analysis. The isolated compounds (1-19) were tested for antifungal activity against human fungal pathogens Cryptococcus neoformans and Candida albicans. Compounds (±)-1 and 8 showed antifungal activity against C. neoformans, with the lowest minimum inhibitory concentrations of 1.8-1.9 μM, which was ∼10-fold lower than that of the currently available antifungal drug fluconazole, while (±)-1, 8, and 19 showed antifungal activity against C. albicans.

1H and 13C NMR spectra of Strychnos alkaloids: Selected NMR updates

AbstractThe PBE0/pcSseg‐2//pcseg‐2 calculations of 1H and 13C NMR chemical shifts were performed for a classical series of 12 Strychnos alkaloids (except for the earlier studied parent strychnine), namely akuammicine, isostrychnine, rosibiline, tsilanine, spermostrychnine, diaboline, cyclostrychnine, henningsamide, strychnosilidine, strychnobrasiline, holstiine, and icajine. It was found that the calculated 1H and 13C NMR chemical shifts show markedly good correlations with available experimental data, as characterized by a mean absolute error of 0.22 ppm for the range of 8 ppm for protons and 1.97 ppm for the range of 180 ppm for carbons. Complementarily, the present results provide essential NMR update and fill a gap in the NMR data of this distinguished group of vitally important natural products.

Metabolite Structure Assignment Using In Silico NMR Techniques.

A major challenge for metabolomic analysis is to obtain an unambiguous identification of the metabolites detected in a sample. Among metabolomics techniques, NMR spectroscopy is a sophisticated, powerful, and generally applicable spectroscopic tool that can be used to ascertain the correct structure of newly isolated biogenic molecules. However, accurate structure prediction using computational NMR techniques depends on how much of the relevant conformational space of a particular compound is considered. It is intrinsically challenging to calculate NMR chemical shifts using high-level DFT when the conformational space of a metabolite is extensive. In this work, we developed NMR chemical shift calculation protocols using a machine learning model in conjunction with standard DFT methods. The pipeline encompasses the following steps: (1) conformation generation using a force field (FF)-based method, (2) filtering the FF generated conformations using the ASE-ANI machine learning model, (3) clustering of the optimized conformations based on structural similarity to identify chemically unique conformations, (4) DFT structural optimization of the unique conformations, and (5) DFT NMR chemical shift calculation. This protocol can calculate the NMR chemical shifts of a set of molecules using any available combination of DFT theory, solvent model, and NMR-active nuclei, using both user-selected reference compounds and/or linear regression methods. Our protocol reduces the overall computational time by 2 orders of magnitude over methods that optimize the conformations using fully ab initio methods, while still producing good agreement with experimental observations. The complete protocol is designed in such a manner that makes the computation of chemical shifts tractable for a large number of conformationally flexible metabolites.

Leishmanicidal Activity of a Quinone Methide Triterpenoid from the roots of Senna spectabilis var. excelsa (Fabaceae)

From an extract of the roots of Senna spectabilis var. excelsa (Fabaceae) , eight known metabolites including the quinone methide triterpenoid 17-(methoxycarbonyl)-28- nor -isoiguesterin ( 1 ) and friedelin ( 2 ), a putative biosynthetic precursor of this class of metabolites, were isolated by applying several chromatographic methods. The structures of the isolated metabolites were established by High Resolution NMR and MS analysis, and confirmed by comparison of their experimental spectroscopic and physical data with those previously reported in the literature. The 2D structure and relative configuration of metabolite 1 were initially determined via analysis of NOESY experiment and confirmed by quantum mechanics-based 13 C NMR chemical shift calculations. Metabolite 1 showed a potent leishmanicidal activity against Leishmania amazonensis and L. brazilensis , with the IC 50 values 9.6 and 6.3 μM, respectively, comparable with the positive control miltefosine (IC 50 values 12.5 and 12.0 μM, respectively), a currently used agent for leishmaniosis treatment. The first example of the occurrence of a quinone methide triterpenoid in species belonging to the Fabaceae family and the first leishmanicidal activity of metabolite 1 are reported in this paper.

Calculating nuclear magnetic resonance chemical shifts in solvated systems

Calculated NMR chemical shifts can be a valuable resource for peak assignments as well as structure determination. Chemical shifts are extremely sensitive to the chemical environment surrounding the nucleus of interest and can be used to deduce precise intramolecular and intermolecular structural information. However, the chemical shift is also very sensitive to solvent effects, conformational and rovibrational averaging, and relativistic effects. All of these effects must be taken into account when calculating magnetic shielding and chemical shift. Here, we review the current state of NMR chemical shift and shielding calculations for solvated systems. Dr. Leah B. Casabianca received her PhD in Physical Chemistry in 2008 working with Prof. Angel C. de Dios at Georgetown University. She then did a postdoctoral fellowship at the University of Illinois at Chicago with Prof. Yoshitaka Ishii working on solid-state NMR of materials and one at the Weizmann Institute of Science with Prof. Lucio Frydman working on Dynamic Nuclear Polarization of rare nuclei. She joined the faculty at Clemson University in 2014. Her work involves developing NMR methods for characterization of molecules interacting with the surface of nanoparticles. Dr. Casabianca was the recipient of an NSF CAREER Award in 2018.

Aspeterreurone A, a Cytotoxic Dihydrobenzofuran-Phenyl Acrylate Hybrid from the Deep-Sea-Derived Fungus Aspergillus terreus CC-S06-18.

A new dihydrobenzofuran-phenyl acrylate hybrid, aspeterreurone A (1), was obtained from the culture of the deep-sea-derived fungus Aspergillus terreus CC-S06-18. The relative configuration of 1 was elucidated by HSQMBC NMR, calculated NMR chemical shifts coupled with a statistical procedure (DP4+), and the absolute configuration was established by ECD calculations. 1 exhibited cytotoxicities against the gastric cancer cell lines HGC27, MGC803, BGC823, and AGS, with minimal effects on normal gastric epithelial cell line GES-1. Further studies showed that 1 inhibited cell cycle progression and induced apoptosis of gastric cancer MGC803 cells in a concentration-dependent manner. Western blot analysis indicated that 1 inhibited the phosphorylation of STAT3, which might contribute to its cytotoxic activity.

DFT-supported structure determination of gymunomitr-3(15)-en-4b,9b-diol

The investigation of the relative and absolute configuration of gymnomitr-3(15)-en-4β,9β-diol (1), a metabolite isolated from the culture medium of Calcarisporium arbuscula, is described. Since the pseudosymmetry of 1 hindered its configurational elucidation based on conventional spectral analysis, we resorted to DFT (Density Functional Theory)-based 13C NMR chemical shift calculations, which allowed identifying the rel-(2S,4R,6S,7R,9R,11S)-form as the candidate isomer giving 99.6% DP4 probability among the eight possible diastereomers. However, the root mean square value of its diastereomer at C-9 was also within the allowable level (1.9 ppm), considering the accuracy of this calculation method (around 2.0 ppm). The latter diastereomer could be ruled out by comparing the calculated 3JH-9/C-7 and 3JH-9/C-11 values with the intensities of the corresponding HMBC (Heteronuclear Multiple Bond Coherence) signals. The absolute configuration was established by reproducing the ECD (Electronic Circular Dichroism) spectrum of the dibenzoyl derivative 2. The biosynthesis of 1 is also discussed.

Phenolics from Archidendron clypearia (Jack) I.C.Nielsen protect SH-SY5Y cells against H2O2-induced oxidative stress

Five undescribed phenolics named pithecellobiumin C-G, along with thirteen known ones were isolated from the twigs and leaves of Archidendron clypearia (Jack) I.C.Nielsen. Their structures were elucidated based on comprehensive spectroscopic analyses, combined with computer-assisted structure elucidation software (ACD/Structure Elucidator) and gauge-independent atomic orbitals (GIAO) NMR chemical shift calculations. The absolute configurations were determined by comparison of experimental and calculated specific rotation and ECD curves. These compounds were tested for their neuroprotective activities against H2O2-induced injury in human neuroblastoma SH-SY5Y cells by MTT assay. Pithecellobiumin C-E exhibited noticeable neuroprotective effect. Further pharmacological study demonstrated that they could prevent cell death through inhibiting the apoptosis induction. Flow cytometry assays also proved that these compounds could attenuate reactive oxygen species (ROS) level and mitochondrial dysfunction in SH-SY5Y cells.

Comparative study of p-phenylenediamine antioxidant effectiveness in styrene-butadiene and polyisoprene rubber through NMR calculations

Structures of six p-phenylenediamine (PPD) antioxidants were optimized and their NMR shifts were evaluated by B3LYP calculations. The dependences of experimental values of Antioxidant Effectiveness (AEX) and Molar Antioxidant Effectiveness (AEM) in styrene-butadiene (SBR) and polyisoprene (PIR) rubber on the calculated NMR chemical shifts of nitrogens, tertiary carbons and hydrogens bonded to them were investigated by means of a multiple linear regression analysis. Based on regression parameter values, the significance of the N centers between aromatic rings (A) seems to be higher than of the N centers between aromatic rings and aliphatic chains (B) except AEM data in PIR. The extent of shielding the A center activity by the cumyl group in ortho-position was estimated. Regression parameters obtained for SBR are significantly higher than for PIR.

Quantum Chemical Calculations of 31P NMR Chemical Shifts in Nickel Complexes: Scope and Limitations

The scope and limitations of a simple approach for the 31P NMR chemical shift calculations of phosphorus atoms directly involved in the formation of coordination bonds with Ni have been analyzed. A...

Triazole based azo molecules as potential antibacterial agents: Synthesis, characterization, DFT, ADME and molecular docking studies

In this study, three triazole based azo molecules [3-amino-4-[1H-1,2,4-triazole-3-yldiazenyl]-1H-pyrazole-5-ol (1), 3-[(3,5-dimethyl-1H-pyrazole-4-yl)diazenyl]-1H-1,2,4-triazole (2) and 4-[1H-1,2,4-triazole-3yldiazenyl]benzene-1,3-diol (3)] were, synthesized and characterized by using 1H NMR, FT-IR, UV–vis and mass spectra. The molecular structure, vibrational spectroscopic data, electronic transition absorption wavelengths, HOMOs and LUMOs analyses, molecular electrostatic potential (MEP) and potential energy surface (PES) diagrams were calculated by using DFT/B3LYP method with 6-311G(d,p) basis set. NMR chemical shift calculations were performed by using the gauge-invariant atomic orbital (GIAO) method. The spectroscopic results obtained from quantum chemical calculations of the 1, 2 and 3 molecules were in good agreement with the experimental data. Antibacterial activities of the 1, 2 and 3 were investigated against four different bacterial cultures. Although 1 molecule did not show very good antibacterial activity, 2 and 3 showed good activity against Staphylococcus aureus at a MIC of 250 and 62.5 μg/mL, respectively. Druglikeness and some of the pharmacokinetic properties of the 1, 2 and 3 were also examined. In addition, molecular docking studies were performed to investigate the antibacterial properties of synthesized compounds by in silico method. For this purpose, β-ketoacyl-acyl carrier protein (ACP) synthase III (KAS III) and lipoteichoic acid synthase (LtaS) inhibitory properties of 1, 2 and 3 molecules were investigated. Although all of the synthesized compounds showed antibacterial properties according to the results of the molecular docking studies, the best results were obtained by the compound 3 which interacts with both KAS III and LtaS with binding energy of −7.17 and −7.53 kcal/mol, respectively.

Assignment of the relative stereochemistry of two novel vicinal dibromo compounds using NMR and DFT-GIAO calculations

Bromination reactions are among the most important reactions in organic synthesis and can be carried out using bromine or many other bromine donor compounds. Among them, one of the best known is the addition of bromine to the C–C double bond to provide vicinal dibromides. Although the classical mechanism indicates the formation of bromonium ion as intermediate of the reaction delivering products in a stereospecific way, some substrates may lead to the mechanism via carbocation or may still have competition between the two types of mechanism. In this work, the addition of bromine to (2E,4E)-N-butylhexa-2,4-dienamide (1) produced erythro and threo diastereoisomers that were identified by comparing the experimental and calculated NMR chemical shifts. The theoretical values were obtained employing DFT-GIAO method and the comparisons were made using MAE values, CP3, and DP4 probabilities. For a better understanding of the bromination of 1, rate-limiting step and reaction energies were calculated for both mechanisms via bromonium and via carbocation.

Accordion-like effect of flexible organic structure-directing agents in the synthesis of ferrierite zeolite

Abstract Ferrierite zeolite was synthesized by a co-structure-directing route using a highly flexible diquaternary ammonium cation (N,N′-bis-triethylpentanediyldiammonium) as a structure directing agent in combination with tetramethylammonium as a small co-structure-directing agent. Strong alterations of the 13C NMR bands of the bulky organic dication upon confinement within the ferrierite framework suggest a change of conformation driven by host-guest interactions. A combination of molecular mechanics and DFT calculations of the theoretical 13C NMR chemical shifts allowed to explain the observed differences in the NMR bands of the dication in solution and when hosted in ferrierite: upon confinement, the flexible dication needs to squeeze through the flexible pentyl chain which locates along the 10 MR ferrierite channels in order to host the two bulky triethyl ammonium groups in adjacent intersections with 8 MR channels. Our work suggests that highly flexible cations, usually considered as less convenient organic structure-directing agents because of low specificity, have the advantage of being able to properly fit with different zeolite cell dimensions through an accordion-like effect by squeezing or stretching their flexible chains.

Megastigmane Derivatives from the Cladodes of Opuntia humifusa and Their Nitric Oxide Inhibitory Activities in Macrophages

Opuntia humifusa, known as the eastern prickly pear cactus and locally called "Cheonnyuncho" in Korea, is cultivated widely on Jeju Island, Korea. Phytochemical analysis of the methanolic extract of the cladodes of O. humifusa, for which previous research is relatively limited, was performed under the guidance of LC/MS-based analysis. As a result, one new megastigmane (1) and four new megastigmane glucosides (2-5) were isolated along with 18 known compounds (6-23). The structures of the new compounds were established by 1D and 2D NMR and HRESIMS, and their absolute configurations were established by chemical reactions, quantum chemical electronic circular dichroism calculations, and DP4+ analysis using the gauge-including atomic orbital NMR chemical shift calculations as well as the application of Snatzke's method. The isolated compounds (1-23) were tested for NO production inhibition in lipopolysaccharide (LPS)-induced RAW 264.7 cells to investigate their anti-inflammatory effects. Compounds 10 and 11 exhibited significant inhibitory effects on LPS-induced NO production in a dose-dependent manner. The potential mechanistic pathway of 10 and 11 was also investigated using Western blotting, indicating that compounds 10 and 11 inhibit NO through iNOS expression.

Ochuscins A‒G, highly oxygenated usnic acid derivatives from the deep-sea-derived fungus Ochroconis sp. FS449

Ochuscins A‒G (1–7), seven highly oxygenated usnic acid derivatives were isolated from the deep-sea-derived fungus Ochroconis sp. FS449. Their structures were elucidated based on the 1D, 2D NMR, HRESIMS and single crystal X-ray diffraction, while the absolute configurations were established by the quantum chemical calculations of 13C NMR chemical shifts as well as ECD plots. The biosynthesis pathway of 1‒7 was proposed to generate via a dimerization of phloroglucinol derivatives. In the bioassay, compounds 2, 3, 4 and 7 exhibited moderate inhibitory activities against acetylcholinesterase with the IC50 values in the range from 49 to 80 μM. A preliminary structure-activity relationship was discussed.

C–P vs C–H Bond Cleavage of Triphenylphosphine at Platinum(0): Mechanism of Formation, Reactivity, Redox Chemistry, and NMR Chemical Shift Calculations of a μ-Phosphanido Diplatinum(II) Platform

Transition-metal phosphanides M–PR2 are key intermediates in catalytic C–P bond functionalization. M–PR2 formation from tertiary phosphines through P–C bond cleavage widens the scope beyond P–H fun...