NMR Chemical Shifts Research Articles

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.

Highly Accurate Prediction of NMR Chemical Shifts from Low-Level Quantum Mechanics Calculations Using Machine Learning.

Theoretical predictions of NMR chemical shifts from first-principles can greatly facilitate experimental interpretation and structure identification of molecules in gas, solution, and solid-state phases. However, accurate prediction of chemical shifts using the gold-standard coupled cluster with singles, doubles, and perturbative triple excitations [CCSD(T)] method with a complete basis set (CBS) can be prohibitively expensive. By contrast, machine learning (ML) methods offer inexpensive alternatives for chemical shift predictions but are hampered by generalization to molecules outside the original training set. Here, we propose several new ideas in ML of the chemical shift prediction for H, C, N, and O that first introduce a novel feature representation, based on the atomic chemical shielding tensors within a molecular environment using an inexpensive quantum mechanics (QM) method, and train it to predict NMR chemical shieldings of a high-level composite theory that approaches the accuracy of CCSD(T)/CBS. In addition, we train the ML model through a new progressive active learning workflow that reduces the total number of expensive high-level composite calculations required while allowing the model to continuously improve on unseen data. Furthermore, the algorithm provides an error estimation, signaling potential unreliability in predictions if the error is large. Finally, we introduce a novel approach to keep the rotational invariance of the features using tensor environment vectors (TEVs) that yields a ML model with the highest accuracy compared to a similar model using data augmentation. We illustrate the predictive capacity of the resulting inexpensive shift machine learning (iShiftML) models across several benchmarks, including unseen molecules in the NS372 data set, gas-phase experimental chemical shifts for small organic molecules, and much larger and more complex natural products in which we can accurately differentiate between subtle diastereomers based on chemical shift assignments.

Engleromophilane, a new broad spectrum bioactive eremophilane-type sesquiterpene from Engleromyces sinensis fungus

A new eremophilane sesquiterpene, named engleromophilane (1) together with known eremoxylarin E (2) and steroids (3-7) were isolated from the fungus Engleromyces sinensis culture. The structures were deduced by the analysis of spectroscopic and MS data, together with the comparison of calculated 13C NMR chemical shifts and Electronic Circular Dichroism (ECD) spectra. Compound 1 showed cytotoxic effects against Hela, PC-3, HT29 and A549 cell lines with IC50 in the ranges of 4.84–9.48 μg/mL. Compounds 1 and 2 exhibited substantial antimicrobial activity against E. coli, S. aureus, and B. subtilis. Moreover, compounds 1–3 showed α-glucosidase inhibitory activity, in which 2 displayed a strong inhibitory effect with an IC50 value of 0.13 ± 0.01 µg/mL. This work has given additional value to the E. sinensis fungus as a remarkable bioactive compound producer, together with the possibility of increasing cultivation to industrial scales.

Molecular Dynamic, Hirshfeld Surface, Computational Quantum and Spectroscopic analysis of 4-Hydroxy-1-Naphthaldehyde

aims: Computational Quantum and Spectroscopic analysis of 4-Hydroxy-1-Naphthaldehyde Background: Known also as 4-Hydroxynaphthalene-1-carbaldehyde, 4-hydroxy-1-naphthaldehyde (4H1NA) is a crucial precursor of many coordinating agents. A commercial compound called 4-hydroxy-1-naphthaldehyde (4H1NA) can be used to make a number of different sensors. In the development of many chemosensors, they operate effectively as a functionalized fluorescent backbone. Objectives: Molecular Dynamic, Hirshfeld Surface, Computational Quantum analysis of Naphthalde-hyde. Methods: The methods employed in the analysis of the compound involve the DFT calculations, using the DFT method and B3LYP/6-311++G (d, p) basis set with respect to its FTIR, NMR, and UV-Visible spectrum. The NMR chemical shifts of carbon and protons in CDCl3 were determined by the GIAO method. For the molecule of reference, HOMO-LUMO and Donor-Acceptor interactions were also taken into consideration. Investigations also looked into E.L.F., Fukui activity, and non-linear optical properties. Results: The investigation of compounds at their atomic level was analyzed using computational methods so that chemical, medicinal, and environmental research make use of them to make the molecule more in an improved form with distinguished properties. Strong interaction has been produced as a result of electron transfer from the oxygen atoms lone pair LP (2) to the anti-bonding orbital *(C3-C5) with a significant stabilization energy of 42.61kcal/mol. The attributes of the NLO molecule were calculated and found to be superior to those of the urea molecule, with linear and first-order hyperpolarizability situations. Our findings imply that the reference molecule can be a heavier contender for NLO as a surface material and could be considered a vital substance for medical purposes in the drug industry due to its maximum electrophilicity index. Conclusion: A commercial compound called 4-hydroxy-1-naphthaldehyde (4H1NA) can be used to make several different sensors. The compound has good structural and optical properties. They can be employed for a variety of optical limiting applications because of their unusual optical characteristic, which exhibits third-order non-linear behavior.

Role of Non‐Covalent Interactions on Acid Strength Measurement of Liquid Acids using Phosphine Oxide NMR Probe

AbstractThe 31P NMR Chemical Shifts(δP) of Trimethylphosphine Oxide (TMPO) conjugated with ten common liquid molecular acids have been calculated employing the Density Functional Theory (DFT) based computational method. These shifts have been correlated with the intrinsic acid strength parameter, Deprotonation Energy (DPE), of the underlying acids and the complexation energy of TMPO (ΔΕ). The acids, anions, and conjugated complexes were modeled with PW91 functional and 6‐31++G(d,p) basis set. The NMR calculations were performed on the relaxed structures as single‐point calculations using the Gauge Including Atomic Orbital (GIAO) method at the MP2 level and TZVP basis set. Poor linearity was observed in the correlation of δP with respect to DPE (R2=0.867), while strong linearity was seen with the complexation energy ΔΕ (R2=0.967). We have hypothesized the unreliable modeling of anions and Non‐Covalent Interactions (NCI) to be the factors affecting the linear trend of δP with respect to DPE. To support our hypothesis, we have presented Reduced Density Gradient (RDG) Maps and 31P NMR Tensor spatial orientation data of the Acid‐TMPO conjugates.

Next-Generation Tags for Fluorine Nuclear Magnetic Resonance: Designing Amplification of Chemical Shift Sensitivity.

Fluorine NMR is a highly sensitive technique for delineating the conformational states of biomolecules and has shown great utility in drug screening and in understanding protein function. Current fluorinated protein tags leverage the intrinsic chemical shift sensitivity of the 19F nucleus to detect subtle changes in protein conformation and topology. This chemical shift sensitivity can be amplified by embedding the fluorine or trifluoromethyl reporter within a pyridone. Due to their polarizability and rapid tautomerization, pyridones exhibit a greater range of electron delocalization and correspondingly greater 19F NMR chemical shift dispersion. To assess the chemical shift sensitivity of these tautomeric probes to the local environment, 19F NMR spectra of all possible monofluorinated and trifluoromethyl-tagged versions of 2-pyridone were recorded in methanol/water mixtures ranging from 100% methanol to 100% water. 4-Fluoro-2-pyridone and 6-(trifluoromethyl)-2-pyridone (6-TFP) displayed the greatest sensitivity of the monofluorinated and trifluoromethylated pyridones, exceeding that of known conventional CF3 reporters. To evaluate the utility of tautomeric pyridone tags for 19F NMR of biomolecules, the alpha subunit of the stimulatory G protein (Gsα) and human serum albumin (HSA) were each labeled with a thiol-reactive derivative of 6-TFP and the spectra were recorded as a function of various adjuvants and drugs. The tautomeric tag outperformed the conventional tag, 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide through the improved resolution of several functional states.

Structure Revision of Formyl Phloroglucinol Meroterpenoids: A Unified Approach Using NMR Fingerprinting and DFT NMR and ECD Analyses

NMR fingerprints are valuable tools for analyzing complex natural product mixtures and identifying incorrectly assigned structures in the literature. Our diagnostic NMR fingerprints for formyl phloroglucinol meroterpenoids revealed discrepancies in the structures reported for eucalyprobusal C (1a) and eucalypcamal K (2a). NMR fingerprinting PCA analyses identified 1a as an oxepine-diformyl phloroglucinol and 2a as an oxepine 3-acyl-1-formyl phloroglucinol, contrary to their initial assignments as pyrano-diformyl and pyrano 3-acyl-1-formyl phloroglucinols, respectively. Extensive reinterpretation of their reported one- and two-dimensional NMR data, coupled with GIAO DFT-calculated 1H and 13C NMR chemical shift and DP4+ analyses, supported the unequivocal reassignment of eucalyprobusal C to 1b and eucalypcamal K to 2b. The absolute configurations of the revised oxepine-containing phloroglucinol meroterpenoids were confirmed via the reinterpretation of their reported ROESY and NOESY NMR data, along with comparative TDDFT-calculated and experimental ECD spectra.

Synthesis, spectroscopic characterisation, DFT insight, and molecular docking studies of a coumarin derivative 3-acetyl-2-oxo-2H-chromene-6-carbohydrazide

In this study, a coumarin derivative, 3-Acetyl-2-oxo-2H-chromene-6-carbohydrazide that could be a new antifungal agent was synthesised, and characterised by elemental analysis, FT-IR, 1H and 13C NMR spectroscopic techniques. DFT calculation data (IR, 1H, and 13C NMR chemical shifts) reveals the good correlation with the experimental values to support the structure of the compound. Molecular geometry, stability, reactivity, and spontaneity were also predicted based on frontier molecular orbitals (FMO), electrostatic potential (ESP) and thermodynamic parameters like entropy, enthalpy, and Gibbs free energy. In addition, molecular docking study results implicate its strong binding (−7.1 to −7.8 kcal/mol) and inhibitory activity against four pathogenic fungal strains A. niger (5GHL), P. chrysogenum (3A72), S. cerevisiae (4G4S), and N. crassa (6MVJ). Thus, this compound may be considered biologically important and serve as a lead for the development of antifungal agents.

Conformational Preferences at the Glycosidic Linkage of Saccharides in Solution as Deduced from NMR Experiments and MD Simulations: Comparison to Crystal Structures.

Glycans are central to information content and regulation in biological systems. These carbohydrate molecules are active either as oligo- or polysaccharides, often in the form of glycoconjugates. The monosaccharide entities are joined by glycosidic linkages and stereochemical arrangements are of utmost importance in determining conformation and flexibility of saccharides. The conformational preferences and population distributions at the glycosidic torsion angles φ and ψ have been investigated for O-methyl glycosides of three disaccharides where the substitution takes place at a secondary alcohol, viz., in α-l-Fucp-(1→3)-β-d-Glcp-OMe, α-l-Fucp-(1→3)-α-d-Galp-OMe and α-d-Glcp-(1→4)-α-d-Galp-OMe, corresponding to disaccharide structural elements present in bacterial polysaccharides. Stereochemical differences at or adjacent to the glycosidic linkage were explored by solution state NMR spectroscopy using one-dimensional 1 H,1 H-NOESY NMR experiments to obtain transglycosidic proton-proton distances and one- and two-dimensional heteronuclear NMR experiments to obtain 3 JCH transglycosidic coupling constants related to torsion angles φ and ψ. Computed effective proton-proton distances from molecular dynamics (MD) simulations showed excellent agreement to experimentally derived distances for the α-(1→3)-linked disaccharides and revealed that for the bimodal distribution at the ψ torsion angle for the α-(1→4)-linked disaccharide experiment and simulation were at variance with each other, calling for further force field developments. The MD simulations disclosed a highly intricate inter-residue hydrogen bonding pattern for the α-(1→4)-linked disaccharide, including a nonconventional hydrogen bond between H5' in the glucosyl residue and O3 in the galactosyl residue, supported by a large downfield 1 H NMR chemical shift displacement compared to α-d-Glcp-OMe. Comparison of population distributions of the glycosidic torsion angles φ and ψ in the disaccharide entities to those of corresponding crystal structures highlighted the potential importance of solvation on the preferred conformation.

Dissociation Kinetics and Antimicrobial Activity of Ofloxacin Antibiotic in Artificial Tears Via 1H-NMR, Raman, and UV-Vis Spectroscopic Analysis.

Introduction: The hydrogen-bonded networks play a significant role in influencing several physicochemical properties of ofloxacin in artificial tears (ATs), including density, pH, viscosity, and self-diffusion coefficients. The activities of the ofloxacin antibiotic with Ats mixtures are not solely determined by their concentration but are also influenced by the strength of the hydrogen bonding network which highlight the importance of considering factors such as excessive tear production and dry eye conditions when formulating appropriate dosages of ofloxacin antibiotics for eye drops. Objectives: Investigating the physicochemical properties of ofloxacin-ATs mixtures, which serve as a model for understanding the impact of hydrogen bonding on the antimicrobial activity of ofloxacin antibiotic eye drops. Determine the antimicrobial activities of the ofloxacin-Ats mixture with different concentration of ofloxacin. Methods: The ofloxacin-ATs mixtures were analyzed using 1H-NMR, Raman, and UV-Vis spectroscopies, with variation of ofloxacin concentration to study its dissociation kinetics in ATs, mimicking its behavior in human eye tears. The investigation includes comprehensive analysis of 1H-NMR spectral data, self-diffusion coefficients, Raman spectroscopy, UV-Vis spectroscopy, liquid viscosity, and acidity, providing a comprehensive assessment of the physicochemical properties. Results: Analysis of NMR chemical shifts, linewidths, and self-diffusion coefficient curves reveals distinct patterns, with peaks or minima observed around 0.6 ofloxacin mole fraction dissociated in ATs, indicating a strong correlation with the hydrogen bonding network. Additionally, the pH data exhibits a similar trend to viscosity, suggesting an influence of the hydrogen bonding network on protonic ion concentrations. Antibacterial activity of the ofloxacin-ATs mixtures is evaluated through growth rate analysis against Salmonella typhimurium, considering varying concentrations with mole fractions of 0.1, 0.4, 0.6, 0.8, and 0.9. Conclusions: The antibiotic-ATs mixture with a mole fraction of 0.6 ofloxacin exhibited lower activity compared to mixtures with mole fractions of 0.1 and 0.4, despite its lower concentration. The activities of the mixtures are not solely dependent on concentration but are also influenced by the strength of the hydrogen bonding network. These findings emphasize the importance of considering tear over-secretion and dry eye problems when designing appropriate doses of ofloxacin antibiotics for eye drop formulations.

The Impact of ortho-substituents on Bonding in Silver(I) and Halogen(I) Complexes of 2-Mono- and 2,6-Disubstituted Pyridines: An In-Depth Experimental and Theoretical Study.

The coordination nature of 2-mono- and 2,6-disubstituted pyridines with electron-withdrawing halogen and electron-donating methyl groups for [N-X-N]+ (X=I, Br) complexations have been studied using 15 N NMR, X-ray crystallography, and Density Functional Theory (DFT) calculations. The 15 N NMR chemical shifts reveal iodine(I) and bromine(I) prefer to form complexes with 2-substituted pyridines and only 2,6-dimethylpyridine. The crystalline halogen(I) complexes of 2-substituted pyridines were characterized by using X-ray diffraction analysis, but 2,6-dihalopyridines were unable to form stable crystalline halogen(I) complexes due to the lower nucleophilicity of the pyridinic nitrogen. In contrast, the halogen(I) complexes of 2,6-dimethylpyridine, which has a more basic nitrogen, are characterized by X-crystallography, which complements the 15 N NMR studies. DFT calculations reveal that the bond energies for iodine(I) complexes vary between -291 and -351 kJ mol-1 and for bromine between -370 and -427 kJ mol-1 . The bond energies of halogen(I) complexes of 2-halopyridines with more nucleophilic nitrogen are 66-76 kJ mol-1 larger than those of analogous 2,6-dihalopyridines with less nucleophilic nitrogen. The experimental and DFT results show that the electronic influence of ortho-halogen substituents on pyridinic nitrogen leads to a completely different preference for the coordination bonding of halogen(I) ions, providing new insights into bonding in halogen(I) chemistry.

A New Series of Sandwich-Type 5,5'-Biterphenylenes: Synthetic Challenge, Structural Uniqueness and Photodynamics.

A new series of biaryls, bi-linear-terphenylenes (BLTPs), were prepared using the tert-butyllithium-mediated cyclization as the key synthetic step. The three-dimensional structures of the studied compounds were verified using X-ray crystallography and DFT calculations. Tetraaryl(ethynyl)-substituted BLTPs are highly crowded molecules, and the internal rotation around the central C-C bond is restricted due to a high barrier (>50 kcal/mol). These structures contain several aryl/terphenylenyl/aryl sandwiches, where the through-space π-π (TSPP) interactions are strongly reflected in the shielding of 1 H NMR chemical shifts, reduction of oxidation potentials, increasing aromaticity of the central six-membered ring and decreasing antiaromaticity of the four-membered rings in a terphenylenyl moiety based on NICS(0) and iso-chemical shielding surfaces. Despite the restricted C-C bond associated intramolecular TSPP interactions for BLTPs in the ground state, to our surprise, the electronic coupling between two linear terphenylenes (LTPs) in BLTPs in the excited state is weak, so that the excited-state behavior is dominated by the corresponding monomeric LTPs. In other words, all BLTPs undergo ultrafast relaxation dynamics via strong exciton-vibration coupling, acting as a blue-light absorber with essentially no emission.

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.

Beyond slow two-state protein conformational exchange using CEST: applications to three-state protein interconversion on the millisecond timescale.

Although NMR spectroscopy is routinely used to study the conformational dynamics of biomolecules, robust analyses of the data are challenged in cases where exchange is more complex than two-state, such as when a 'visible' major conformer exchanges with two 'invisible' minor states on the millisecond timescale. It is becoming increasingly clear that chemical exchange saturation transfer (CEST) NMR experiments that were initially developed to study systems undergoing slow interconversion are also sensitive to intermediate-fast timescale biomolecular conformational exchange. Here we investigate the utility of the amide 15N CEST experiment to characterise protein three-state exchange occurring on the millisecond timescale by studying the interconversion between the folded (F) state of the FF domain from human HYPA/FBP11 (WT FF) and two of its folding intermediates I1 and I2. Although 15N CPMG experiments are consistent with the F state interconverting with a single minor state on the millisecond timescale, 15N CEST data clearly establish an exchange process between F and a pair of minor states. A unique three-state exchange model cannot be obtained by analysis of 15N CEST data recorded at a single temperature. However, including the relative sign of the difference in the chemical shifts of the two minor states based on a simple two-state analysis of CEST data recorded at multiple temperatures, results in a robust three-state model in which the F, I1 and I2 states interconvert with each other on the millisecond timescale ( ~ 550s-1, ~ 1200s-1, ~ 5000s-1), with I1 and I2 sparsely populated at ~ 0.15% and ~ 0.35%, respectively, at 15°C. A computationally demanding grid-search of exchange parameter space is not required to extract the best-fit exchange parameters from the CEST data. The utility of the CEST experiment, thus, extends well beyond studies of conformers in slow exchange on the NMR chemical shift timescale, to include systems with interconversion rates on the order of thousands/second.

Cover Feature: Ligand 1H NMR Chemical Shifts as Accurate Reporters for Protein‐Ligand Binding Interfaces in Solution (ChemPhysChem 1/2024)

Cover Feature: Ligand ¹H NMR Chemical Shifts as Accurate Reporters for Protein‐Ligand Binding Interfaces in Solution (ChemPhysChem 1/2024)

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.

NMR analysis of structural geometry and molecular dynamics in perovskite-type N(CH3)4CdBr3 crystal near high-temperature phase transition.

The NMR chemical shifts, linewidths, spin-lattice relaxation times in the rotating system T1ρ, and spin-lattice relaxation times in the laboratory system T1 were evaluated for the perovskite-type N(CH3)4CdBr3 crystal, aiming to understand the changes in the structural geometry and molecular dynamics from phase I to phase II. From the temperature-dependence of the 1H, 13C, 14N, and 113Cd NMR chemical shifts, the structural geometry underwent a continuous change, without anomalous changes around (TC = 390 K). However, the linewidths in phase I were narrower than those in phase II, indicating that the motional averaging effects were caused by the rapid rotation of the N(CH3)4 group. Sudden changes in T1 and T1ρ were observed near TC, for which the activation energy Ea in phase I was approximately 12 times larger than that in phase II; the small Ea values in phase II indicate a large degree of freedom for the methyl group and CdBr6 octahedra, whereas the large Ea in phase I was primarily attributed to the overall N(CH3)4 and the 113Cd in the CdBr6 groups. Consequently, the phase transition mechanisms of N(CH3)4CdBr3 are related to reorientation of the N(CH3)4 group and the arrangement of the CdBr6 groups.