Chemical Shift Variations Research Articles

Direct Estimation of Aromatization Energy from 1H NMR and UV-Vis Absorption Data of Homodesmotic Molecules.

This study delves into the ring-opening reaction of two distinct diaryl-ring-pyran systems, referred to as drnp1 and drnp2, where the term 'ring' encompasses aromatic, nonaromatic, or antiaromatic motifs. These systems transform into the corresponding cis-ortho quinonoid systems, denoted as c-drnq1 and c-drnq2. Homodesmotic pairs (drnp1, drnp2) and (c-drnq1, c-drnq2) are categorized as (aromatic, nonaromatic), (aromatic, partially aromatic), (antiaromatic, nonaromatic), and (nonaromatic, nonaromatic), with their energy difference representing aromatization energy (Earoma). Using reliable density functional theory, Earoma is assessed for various aromatic and antiaromatic ring motifs, including borderline cases and nonaromatic structures. For example, benzene exhibits an Earoma of 23.4 kcal/mol, indicating 3.9 kcal/mol aromatic stabilization per CC bond, while cyclobutadiene shows -29.9 kcal/mol, indicating a 7.5 kcal/mol destabilization of the CC bond. This approach extends to evaluating global and local aromatic stabilization effects in polycyclic hydrocarbons, nonbenzenoid systems, and heterocyclic compounds. Additionally, variation in 1H NMR chemical shift (δavg) correlates with Earoma, suggesting that a -1.0 ppm shift corresponds to 24.2 kcal/mol aromatization energy. UV-vis absorption maxima difference (Δλavg) correlates linearly with Earoma, enabling direct assessment of aromatization energy from UV-vis spectra using suitable homodesmotic pairs. This comprehensive approach enhances our understanding of structural, energetic, and spectroscopic aspects of aromatic and antiaromatic systems.

Solid-State NMR Characterization of Mefloquine Resinate Complexes Designed for Taste-Masking Pediatric Formulations.

Mefloquine (MQ) is an antimalarial medication prescribed to treat or malaria prevention.. When taken by children, vomiting usually occurs, and new doses of medication frequently need to be taken. So, developing pediatric medicines using taste-masked antimalarial drug complexes is mandatory for the success of mefloquine administration. The hypothesis that binding mefloquine to an ion-exchange resin (R) could circumvent the drug's bitter taste problem was proposed, and solid-state 13C cross-polarization magic angle spinning (CPMAS) NMR was able to follow MQ-R mixtures through chemical shift and relaxation measurements. The nature of MQ-R complex formation could then be determined. Impedimetric electronic tongue equipment also verified the resinate taste-masking efficiency in vitro. Variations in chemical shifts and structure dynamics measured by proton relaxation properties (e.g., T1ρH) were used as probes to follow the extension of mixing and specific interactions that would be present in MQ-R. A significant decrease in T1ρH values was observed for MQ carbons in MQ-R complexes, compared to the ones in MQ (from 100-200 ms in MQ to 20-50 ms in an MQ-R complex). The results evidenced that the cationic resin interacts strongly with mefloquine molecules in the formulation of a 1:1 ratio complex. Thus, 13C CPMAS NMR allowed the confirmation of the presence of a binding between mefloquine and polacrilin in the MQ-R formulation studied.

Synergistic exploration of antimicrobial potency, cytotoxicity, and molecular mechanisms: A tripartite investigation integrating in vitro, in vivo, and in silico approaches for pyrimidine‐based metal (II) complexes

We synthesized and characterized bioactive metal (II) complexes from a pyrimidine‐based Schiff base ligand, 4‐[2‐(4‐chlorobenzylidene) hydrazinyl]‐7H‐pyrrolo[2,3‐d]pyrimidine. Through thorough elemental analysis and various physicochemical techniques, we characterized both the ligand and its Zn(II), Cd(II), and Hg(II) complexes. Coordination of the metallic ion was established via nitrogen atoms from the ligand's pyrrolo and pyrimidine rings, yielding tetrahedral complexes of the type [M(PPHpCB)2]. These complexes are identified as non‐electrolytes due to their low molar conductance. Furthermore, we investigated the coordination behavior of the pyrimidine‐based Schiff base ligand (HPPHpCB) with metal ions through comprehensive spectroscopic analysis. 1H NMR spectral data showed bonding between HPPHpCB and metal ions, while UV spectra confirmed intra‐ligand and ligand‐to‐metal charge transfer transitions, indicating coordination through nitrogen atoms. The determination of tetrahedral geometry for metal complexes confirmed their diamagnetic properties. Analysis using 13C NMR and electrospray ionization mass spectra (ESI‐MS) revealed variations in chemical shifts, confirming successful complex formation and elucidating structural modifications, electronic interactions, and metal–ligand coordination modes. Moreover, evaluation of in vitro antimicrobial activities using the minimum inhibitory concentration (MIC) approach revealed significant antibacterial and antifungal activities for Hg(II) and Cd(II) complexes, respectively. The Hg(II) complex displayed superior antioxidant activity, while Zn(II) and Cd(II) complexes also demonstrated considerable potential. In vivo, cytotoxicity assessments against Artemia salina provided insights into the cytotoxic properties of ligands and metal complexes. Computational techniques suggested their potential in combating infectious ailments. Overall, our study establishes the synthesis, characterization, and multifaceted biological activities of metal (II) complexes derived from the pyrimidine‐based Schiff base ligand, highlighting their promising role in combating various infectious diseases.

NMR Precision Metabolomics: Dynamic Peak Sum Thresholding and Navigators for Highly Standardized and Reproducible Metabolite Profiling of Clinical Urine Samples.

Metabolomics, especially urine-based studies, offers incredible promise for the discovery and development of clinically impactful biomarkers. However, due to the unique challenges of urine, a highly precise and reproducible workflow for NMR-based urine metabolomics is lacking. Using 1D and 2D non-uniform sampled (NUS) 1H-13C NMR spectroscopy, we systematically explored how changes in hydration or specific gravity (SG) and pH can impact biomarker discovery. Further, we examined additional sources of error in metabolomics studies and identified Navigator molecules that could monitor for those biases. Adjustment of SG to 1.002-1.02 coupled with a dynamic sum-based peak thresholding eliminates false positives associated with urine hydration and reduces variation in chemical shift. We identified Navigator molecules that can effectively monitor for inconsistencies in sample processing, SG, protein contamination, and pH. The workflow described provides quality assurance and quality control tools to generate high-quality urine metabolomics data, which is the first step in biomarker discovery.

Investigation on the organic–inorganic hybrid crystal [NH2(CH3)2]2CuBr4: structure, phase transition, thermal property, structural geometry, and dynamics

Understanding the physical properties of the organic–inorganic hybrid [NH2(CH3)2]2CuBr4 is essential to expand its applications. The single [NH2(CH3)2]2CuBr4 crystals were grown and their comprehensive properties were investigated. The crystals had a monoclinic structure with the space group P21/n and lattice constants of a = 8.8651 (5) Å, b = 11.9938 (6) Å, c = 13.3559 (7) Å, and β = 91.322°. The transition temperature from phase I to phase II was determined to be 388 K. Variations in the 1H nuclear magnetic resonance chemical shifts of NH2 and 14N NMR chemical shifts according to the temperature changes in the cation were attributed to vibrations of NH2 groups at their localization sites. The 1H and 13C spin–lattice relaxation times (T1ρ) in phase II changed significantly with temperature, indicating that these values are governed by molecular motion. The T1ρ values were much longer in phase I than in phase II, which means energy transfer was difficult. Finally, the activation energies for phases I and II were considered. According to the basic mechanism of [NH2(CH3)2]2CuBr4 crystals, organic–inorganic materials may have potential applications in various fields.

Core-Level 2s and 2p Binding Energies of Third-Period Elements (P, S, and Cl) Calculated by Hartree-Fock and Kohn-Sham ΔSCF Theory.

In the present study, we investigate the use of the ΔSCF method and Slater's transition state (STS) theory to calculate the binding energies of the 2s and 2p electrons of third-period elements (P, S, and Cl). Both the Hartree-Fock (HF) and Kohn-Sham (KS) approximations are examined. The STS approximation performs well in reproducing the ΔSCF values. However, for the ΔSCF method itself, while the binding energy of the 2p electrons is accurately predicted, the results for 2s are fairly sensitive to the functional, exhibiting significant variations due to self-interaction errors (SIE). Nonetheless, the variations in chemical shifts between different species remain relatively small, and the values agree with experiments due to the cancellation of SIE. A notable observation is that the chemical shifts of the 2s and 2p electrons are similar, indicating a perturbation caused by the valence electrons. The error in the absolute binding energy of KS ΔSCF against the experiment is nearly constant for the same element in different molecules, and it depends largely on the functional owing to SIE. A shifting scheme previously developed can be employed to reproduce the experimental 2s and 2p binding energies, with dependence on the functional and atom but not on the molecule even for 2s KS ΔSCF binding energies. Upon obtaining the corrected binding energies, we find that the gap between 2s and 2p binding energy is nearly independent of chemical environment for a given element: 57.5, 63.9, and 70.9 eV for the elements P, S, and Cl, respectively.

Effects of Sample Dilution on Nuclear Magnetic Resonance-Derived Metabolic Profiles of Human Urine.

Traditionally, a relatively big urine volume (e.g., 500 μL) is used in nuclear magnetic resonance (NMR)-based human metabolomics, which is not feasible for studies with limited/precious samples. Although urine may be diluted before conventional high-throughput metabolomics analysis, the comprehensive effect of urine dilution on metabolic profiles is unknown. Here, for the first time, we systematically investigated the effect of urine dilution on 1H NMR metabolic profiles, by evaluating signal detectability, integration, signal-to-noise ratio (SNR), chemical shift (δ) and its variation, and signal overlapping of 47 metabolites in 10 volunteers. We observed significant linear changes along with increased dilution, including decreased integration and SNR, altered δ, decreased intersample variation of δ, and increased separation between overlapped signals, e.g., lactate and threonine, β-d-glucose and an unassigned signal, and histidine and 3-methylhistidine. We further tested the 40% dilution level (i.e., employing 300 μL urine) in an epidemiological study containing 1018 pregnant women from the Tongji-Shuangliu Birth Cohort, showing acceptable detectability and chemical shift variability for most of the 47 metabolites profiled. It indicated that mild (e.g., 40%) dilution of human urine can largely preserve the high-abundance metabolites profiled, reduce intersample chemical shift variations, and increase separations of overlapped signals, which is an improvement of routine sample preparation methods in NMR-based metabolomics and is applicable for studies with limited urine volumes, including large-scale epidemiological studies.

The multiple bond character of the carbon−boron bond in boron trapped N-heterocyclic carbenes (NHCs) and cyclic(alkyl)(amino)carbenes (CAACs) on the magnetic criterion

Geometry, 11B, 13C chemical shifts and the spatial magnetic properties (Through-Space NMR Shieldings − TSNMRS) of both cations and anions of boron-trapped N-heterocyclic carbenes (NHCs) and cyclic (alkyl)(amino)carbenes (CAACs) and of the corresponding diborane/diborene/diboryne dis-carbene adducts have been calculated using the GIAO perturbation method employing the nucleus independent chemical shift (NICS) concept; the TSNMRS results are visualized as iso-chemical-shielding surfaces (ICSS) of various size and direction. The ICSS of the TSNMRS (actually the anisotropy effects measurable in 1H NMR spectroscopy) are employed to qualify and quantify the present multiple bond character of the Carbene−Boron bond in the trapped NHCs and CAACs. Results are confirmed by bond length and 11B/13C chemical shift variations. Thus the partial multiple bond character of the Carbene−Boron bond cannot be expressed by the arrow of weak, much longer dative bonds and should be omitted as in other covalent lone pair-π or triel bonds.

Insights into the self-assembly of fampridine hydrochloride: how the choice of the solvent affects the crystallization of a simple salt

Abstract Crystalline materials and crystallization processes play an important role in several fields of science, such as pharmaceuticals, material science, pigments, optoelectronics, catalysis and energy storage. Understanding and defining the right conditions of crystallization is therefore crucial. Among the several factors influencing the crystallization of a given compound, the choice of the solvent system is perhaps one of the most important. The nature of solvent–solute interactions can indeed have a role in promoting specific molecular assemblies, therefore affecting crystallisation rates of a crystal and often resulting in the nucleation of different polymorphs and solvates. Here we investigated the role of a binary mixture of solvent (water/acetone) in the crystallisation of a simple salt of 4-aminopyridinium chloride. Previous results on this compound showed that when crystallised from water it forms a simple hydrate structure, while in the presence of acetone, it undergoes a liquid-liquid phase separation, followed by the crystallisation of a complex structure belonging to the Frank–Kasper (FK) phases, a particular family of topologically close-packed structures never observed in small and rigid molecules. To broaden the understanding of how such a simple molecule may crystallise as an FK phase, we carried out the crystallization of the complex phase by antisolvent diffusion (in a mixture of water/acetone) and that of the monohydrate phase in water, monitoring the liquid precursors by liquid-state NMR. In particular, we applied 1H, 13C, 14N, 17O, and 35/37Cl NMR as a function of the concentration of 4APH+Cl− until the moment when precipitation of the crystalline phases occurred. Variations of chemical shifts, T1 relaxation times of 13C signals, and full-width at half-maximum of the signals of quadrupolar nuclei were also measured. The spatial proximity between the different species in the solution was investigated by NOE experiments. In order to support these results, we also performed Molecular Dynamics simulations, investigating the potential solute/solvents interactions. The results strongly suggest that acetone, instead of behaving as an anti-solvent, interacts directly with the solute, preventing the formation of the simple monohydrate structure and, at the same time, promoting specific molecular aggregations.

Revealing the Pore Size-Dependent Sorption Mechanism of Toluene and Cetane in Porous Carbon by Nuclear Magnetic Resonance.

The adsorption of contaminants by porous carbon has been extensively studied by conventional isotherm and kinetic methods. However, the co-adsorption behavior and sorption sites of multiple contaminants in different-sized pores remain unclear. Herein, the nuclear magnetic resonance (NMR) approach is performed to investigate the adsorption mechanism of toluene and cetane in the confined space of carbon at the molecular level. The ring current effect induces the variation in the NMR chemical shifts of in-pore adsorbed toluene and cetane, realizing the identification of pore-dependent adsorption sites for contaminant removal. Cetane has a slower adsorption kinetic but a higher binding energy than toluene, which could squeeze toluene from micropores to larger pores with increasing adsorption quantity. This leads to a stronger competitive adsorption effect in small micropores than in mesopores. Accordingly, hierarchical porous carbons are determined to be the most effective adsorbents for the adsorption of coexisting contaminants. This study not only provides an effective NMR method to reveal the adsorption mechanism in the confined space of porous carbon at the molecular level but also offers new insights into the pore size-dependent adsorption of activated carbon for petroleum contaminant treatment.

Probing molecular interactions of amylose-morin complex and their effect on antioxidant capacity by 2D solid-state NMR spectroscopy

Interaction of polyphenols and starch significantly governed the further applications on polyphenol-starchy foods. Elucidation of inter-molecular interaction is, however, a challenge because conventional characterizations could not detect the change of micro-environment caused by weak interactions. Herein, a facile strategy for molecular detection of amylose-polyphenol interactions was reported using two-dimensional solid-state NMR spectroscopy. Amylose-morin complex was prepared and characterized using 1H NMR, FT-IR, DSC, XRD and SEM. Significantly, variation of chemical shifts, splitted peaks and peak width, monitored by 13C CP/MAS and 1H NMR spectra, identified the strong inter-molecular interaction and binding sites. Furthermore, correlated signals from 1H–13C HETCOR confirmed the binding sites of interactions. These findings confirmed the interaction was inter-molecular hydrogen bonds, which generated between hydroxy-3,5,7 of morin and hydroxy groups of amylose. Besides, DPPH radical scavenging and reducing power assay indicated inter-molecular hydrogen bonds are not strong enough to interfere antioxidant capacity of morin.

GIPMA: Global Intensity-Guided Peak Matching and Alignment for 2D 1H-13C HSQC-Based Metabolomics.

Two-dimensional (2D) 1H-13C heteronuclear single quantum coherence (HSQC) has been increasingly applied to metabolomics studies because it can greatly improve the resolving capability compared with one-dimensional (1D) 1H NMR. However, preprocessing methods such as peak matching and alignment tools for 2D NMR-based metabolomics have lagged behind similar methods for 1D 1H NMR-based metabolomics. Correct matching and alignment of 2D NMR spectral features across multiple samples are particularly important for subsequent multivariate data analysis. Considering different intensity dynamic ranges of a variety of metabolites and the chemical shift variation across the spectra of multiple samples, here, we developed an efficient peak matching and alignment algorithm for 2D 1H-13C HSQC-based metabolomics, called global intensity-guided peak matching and alignment (GIPMA). In GIPMA, peaks identified in all spectra are pooled together and sorted by intensity. Chemical shift of a stronger peak is regarded to be more accurate and reliable than that of a weaker peak. The strongest undesignated peak is chosen as the reference of a new cluster if it is not located within the chemical shift tolerance of any existing peak cluster (PC), or otherwise it is matched to an existing PC and the aligned chemical shift of the PC is updated as the intensity-weighted average of the chemical shifts of all peaks in the cluster. Setting an optimum chemical shift tolerance (Δδo) is critical for the peak matching and alignment across multiple samples. GIPMA dynamically searches for and intelligently selects the Δδo for peak matching to maximize the number of valid peak clusters (vPC), that is, spectral features, among multiple samples. By GIPMA, fully automatic peakwise matching and alignment do not require any spectrum as initial reference, while the chemical shift of each PC is updated as the intensity-weighted average of the chemical shifts of all peaks in the same PC, which is warranted to be statistically more accurate. Accurate chemical shifts for each representative spectral feature will facilitate subsequent peak assignment and are essential for correct metabolite identification and result interpretation. The proposed method was demonstrated successfully on the spectra of six model mixtures consisting of seven typical metabolites, yielding correct matching of all known spectral features. The performance of GIPMA was also demonstrated on 2D 1H-13C HSQC spectra of 87 real extracts of 29 samples of five Dendrobium species. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) of the 87 matched and aligned spectra by GIPMA generates correct classification of the 29 samples into five groups. In summary, the proposed algorithm of GIPMA provided a practical peak matching and alignment method to facilitate 2D NMR-based metabolomics studies.

Influence of the filling ratio of vial in chemical surface and physicochemical properties of ZnO nanoparticles obtained by planetary ball milling process

The production of nanoparticles (Np) is an important sector in current technological development. Processes such as high‐energy grinding are among the most promising because of their high efficiency and low energy cost. In this sense, the filling ratio of vial (FRV) is one of the most interesting and poorly studied process variables that can optimize the production of Np on a large scale. In the present work, dry ZnO Np are produced, with different FRV values (40%, 38%, 23%, and 10%), as well as wet samples. The results show that the variation of the FRV allows to generate an energetic increase of the grinding, modifying the morphology, the particle size, and the surface area of the ZnO powders, without generating structural or chemical changes. The X‐ray diffraction (XRD) results show the presence of the zincite phase (hexagonal) with a variation in crystallinity depending on the FRV, which is due to the deformation of the Np during the process. The XPS results showed a slight chemical shift (variation in binding energy) as a function of grinding because of the activation shown by deformation. UV–VIS analyses showed a marked increase in the magnitude of absorbed intensity for all analyzed samples compared with the commercial powder. These results confirm that FRV is a sensitive parameter in the process of obtaining ZnO Np by the planetary mill technique, which allows efficient control of its characteristics for a given application.

Chemical shift variations in common metabolites

The reliability and robustness of metabolite assignments in 1H NMR is complicated by numerous factors including variations in temperature, pH, buffer choice, ionic strength, and mixture composition that led to peak overlap and spectral crowding. As sample conditions fluctuate, peak drift and line broadening further complicate peak deconvolution and subsequent chemical assignment. We present a collection of 1D 1H NMR spectra of 54 common metabolites at varied pH (6.0 to 8.0 in 0.5 step increments) and temperature (290 K to 308 K) to quantify chemical shift variability to facilitate automated metabolite assignments. Our results illustrate the fundamental challenges with accurately assigning NMR peaks under varied environmental conditions prevalent in complex mixtures. Phosphorylated metabolites showed a larger variation in chemical shifts due to pH, whereas; amino acids showed a higher variation due to temperature. Mixtures of phosphorous compounds showed a consistently poor reliability in achieving an accurate assignment. Phosphorylated cholines, amino acids, and glycerols yielded a 40 % false negative rate for 7 out of 9 mixture conditions. Amino acids had a false negative rate of 57 % at 298 K and pH 8. Our results demonstrate that the automated assignments of complex biofluid mixtures require an expert to intervene to confirm the accuracy of metabolite assignments. Our analysis also indicates the need for reference databases to include spectra under a variety of conditions that includes mixtures and a range of pH and temperature to improve the accuracy and reproducibility of metabolite assignments.

Synthesis, crystal structure and NMR-study new mononuclear paramagnetic Er (III) complex based on imine derivatives of thiacalix[4]arene

The synthesis, crystal structure and NMR-study of new paramagnetic Er (III) complex based on imine derivatives of thiacalix[4]arene was carried out. Temperature dependences of the 1H NMR spectra of complex Er(III) and calix[4]arene with N-contained substituents (I) have been analyzed using the line shape analysis, taking into account the temperature variation of paramagnetic chemical shifts, within the frame of the dynamic NMR method. Two kinds of molecular dynamics in I are reported for the CDCl3 solution. The first one conformational dynamics is conditioned by the pinched cone A ↔ pinched cone B interconversion with activation free energy ΔG≠(298 K) = 40 ± 3 kJ/mol (observed at low temperature). The second one dynamics is connected with rearrangements in coordination environment (with ΔG≠(298 K) = 58 ± 3 kJ/mol). Due to substantial temperature dependence of paramagnetic shifts, the complex I can be considered as NMR thermosensor reagent for local temperature monitoring. Owing to the large magnetic moments typical for many Ln-ions and especially high value of magnetic anisotropy for Er cation (III) adopting capped trigonal prismatic geometry of coordination sphere one may expect that 1-Er can potentially exhibit SMM behavior.

NMR studies of Sugammadex formulations complexes with steroidal neuromuscular blockers drugs Rocuronium and Vecuronium

Sugammadex a modified γ-cyclodextrin forms strong water-soluble complexes with steroid neuromuscular blockers (NMBs) such as Rocuronium and Vecuronium, creating a concentration gradient that favors the displacement of these drugs from the neuromuscular junction to the plasma, quickly reversing the neuromuscular obstruction. This work described the comparative evaluation between two formulations of Sugammadex solution from Blau Farmacêutica S/A compared to reference formulation Bridion®, by Nuclear Magnetic Resonance (NMR) 1H and DOSY techniques. The formulations were evaluated in presence of Rocuronium and Vecuronium in the stoichiometric proportions of 1:1 and 1:0.4 for both NMBs. NMR 1H spectra of the formulations Blau and Bridion® did not show significant variations of chemical shifts showing similar physicochemical parameters. Chemical shifts and diffusion coefficients of NMBs were influenced by the presence of Sugammadex when compared to NMBs formulations in the absence of any cyclodextrin, directly demonstrating the strong intermolecular interaction associated with the host molecule in a high proportion. No significant variation in the diffusion coefficients of the key components between formulations in the presence of NMBs in the equimolar 1:1 and 1:04 w/w ratios was observed. The constants Ka and KD were determined and presented 16.7 and 0.06 mM values respectively, according to literature for this system.

NMR Crystallographic Approach to Study the Variation of the Dynamics of Quinine and Its Quasienantiomer Quinidine

The structure and dynamics of quinine and its quasienantiomer quinidine were studied at the atomic resolution by measuring the chemical shift anisotropy (CSA) tensor and site-specific spin–lattice relaxation time. For quinine, there are three crystallographically independent molecules “a”, “b”, and “c” in an asymmetric unit since its 13C CP-MAS SSNMR spectrum features three distinct resonance peaks for certain carbon nuclei. The 13C assignments are fulfilled by DFT calculations. The experimental 13C isotropic chemical shifts well match the calculated values. These variations of isotropic chemical shift for three independent molecules are also observed by two-dimensional 13C–1H heteronuclear correlation spectroscopy (HETCOR) of quinine. The spin–lattice relaxation time, and the principal components of CSA parameters are also varied substantially for certain carbon nuclei of “a”, “b”, and “c” molecules. For quinidine, its 13C CP-MAS SSNMR spectrum is remarkably different from that of quinine despite, their almost identical solution NMR spectra. Furthermore, the remarkable change in the structure and dynamics of quasienantiomers are also observed including the steric effect of the substituent vinyl group, the variation of helical motifs, and the variation of the strength of the intermolecular hydrogen bonds. The variation of the structure and dynamics of quasienantiomers are thoroughly studied by solid-state NMR measurements. These types of studies will enrich the field of NMR crystallography.

Paramagnetic Properties and Moderately RapidConformational Dynamics in the Cobalt(II) Calix[4]arene Complex by NMR.

1H NMR measurements are reported for the CD2Cl2/CDCl3 solutions of the Co(II) calix[4]arenetetraphosphineoxide complex (I). Temperature dependences of the 1H NMR spectra of I have been analyzed using the line shape analysis, taking into account the temperature variation of paramagnetic chemical shifts, within the frame of the dynamic NMR method. Conformational dynamics of the 2:1 Co(II) calix[4]arene complexes was conditioned by the pinched cone ↔pinched cone interconversion of I (with activation Gibbs energy ΔG≠(298K) = 40 ± 3 kJ/mol. Due to substantial temperature dependence of paramagnetic shifts, complex I can be used as model compound for designing an NMR thermosensor reagent for local temperature monitoring.

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation.

The synthesis and conformational analysis of the first series of peptoid oligomers composed of consecutive N-(alkylamino)glycine units is investigated. We demonstrate that N-(methylamino)glycine homooligomers can be readily synthesized in solution using N-Boc-N-methylhydrazine as a peptoid submonomer and stepwise or segment coupling methodologies. Their structures were analyzed in solution by 1D and 2D NMR, in the solid state by X-ray crystallography (dimer 2), and implicit solvent QM geometry optimizations. N-(Methylamino)peptoids were found to preferentially adopt trans amide bonds with the side chain N–H bonds oriented approximately perpendicular to the amide plane. This orientation is conducive to local backbone stabilization through intra-residue hydrogen bonds but also to intermolecular associations. The high capacity of N-(methylamino)peptoids to establish intermolecular hydrogen bonds was notably deduced from pronounced concentration-dependent N–H chemical shift variation in 1H NMR and the antiparallel arrangement of mirror image molecules held together via two hydrogen bonds in the crystal lattice of dimer 2.

Novel Sterically Crowded and Conformationally Constrained α-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells.

In order to discover new 31P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pKas (ranging 6.28–6.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation Δδab between the acidic and basic forms) ranging from 9.2–10.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pKas and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating Δδab. Finally, the hit 31P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pKa = 6.45 with Δδab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of <0.05 pH units.