Selective Nuclear Overhauser Effect Research Articles

NMR evidence for hydrogen bonding stabilized anti conformation of 1-methoxy-1-methyl-3-phenylurea and the concentration detection by SERS

Phenylurea-based herbicides have been widely used to control the plant growth. Due to their toxicity, strict regulations to limit their usage have been applied. Developing trace detection protocols of substituted phenylureas has attracted more attention, especially with the availability of a wide range of spectroscopic and analytical techniques. In this study, the conformational and structural properties of 1-methoxy-1-methyl-3-phenylurea (MMPU) which belongs to the family of phenylurea-based herbicides have been characterized. The anti-configuration, facilitated by the intramolecular hydrogen bonding between the oxygen atom of the methoxy moiety and the acidic amide proton, was observed using the nuclear magnetic resonance (NMR) spectroscopy through the Selective Nuclear Overhauser Effect (SelNOE) approach. The density functional theory (DFT) calculations suggested that the anti form is at least 9 kcal/mol more stable than the corresponding syn structure. Possible degradation pathways of such a class of herbicides can be explored when a firm understanding of their electronic and conformational behaviors is established. The detection of trace MMPU has been successfully developed using the surface-enhanced Raman scattering (SERS) spectroscopic tool. The most enhanced peak associated with the carbonyl group stretching vibration which appears nearly at 1600 cm−1 has presented a Raman enhancement factor of 3.24 × 105 and a micrommolar limit of detection.

Mechanistic Investigation of Drug Supersaturation in the Presence of Polysorbates as Solubilizing Additives by Solution Nuclear Magnetic Resonance Spectroscopy.

The introduction of solubilizing additives has historically been an attractive approach to address the ever-growing proportion of poorly water-soluble drug (PWSD) compounds within the modern drug discovery pipeline. Lipid-formulations, and more specifically micelle formulations, have garnered particular interest because of their simplicity, size, scalability, and avoidance of solid-state limitations. Although micelle formulations have been widely utilized, the molecular mechanism of drug solubilization in surfactant micelles is still poorly understood. In this study, a series of modern nuclear magnetic resonance (NMR) methods are utilized to gain a molecular-level understanding of intermolecular interactions and kinetics in a model system. This approach enabled the understanding of how a PWSD, 17β-Estradiol (E2), solubilizes within a nonionic micelle system composed of polysorbate 80 (PS80). Based on one-dimensional (1D) 1H chemical shift differences of E2 in PS80 solutions, as well as intermolecular correlations established from 1D selective nuclear Overhauser effect (NOE) and two-dimensional NOE spectroscopy experiments, E2 was found to accumulate within the palisade layer of PS80 micelles. A potential hydrogen-bonding interaction between a hydroxyl group of E2 and a carbonyl group of PS80 alkane chains may allow for stabilizing E2-PS80 mixed micelles. Diffusion and relaxation NMR analysis and particle size measurements using dynamic light scattering indicate a slight increase in the micellar size with increasing degrees of supersaturation, resulting in slower mobility of the drug molecule. Based on these structural findings, a theoretical orientation model of E2 molecules with PS80 molecules was developed and validated by computational docking simulations.

Conformational analysis and concentration detection of linuron: Spectroscopic NMR and SERS study

Linuron is a commonly used organic herbicide which is used in plant growth control. Due to its potential health concerns, the characterization and monitoring of linuron have been a subject of several studies. In this work, we employed nuclear magnetic resonance (NMR) and Raman spectroscopic techniques supported with the density functional theory (DFT) to investigate the conformational behavior and electronic aspects of linuron. The selective nuclear Overhauser effect (SelNOE) spectra confirmed that linuron exists predominantly in the anti configuration and is facilitated with a weak intramolecular hydrogen bonding between the acidic amide proton and oxygen of methoxy moiety. Quantum chemical results showed that the corresponding syn form of the molecule is 8.5 kcal/mol less stable. Further, the surface enhanced Raman scattering (SERS) technique using gold nanoparticles (AuNPs) was implemented as a potential spectroscopic protocol for the concentration monitoring of trace linuron. The Raman responses of four vibrational modes, namely CC stretching, CN stretching, N-H rocking and ring deformation, were successfully enhanced with an excellent linear concentration-intensity dependency. The aromatic CC stretching vibration at 1595 cm−1 in the Raman spectra has demonstrated the highest enhancement factor (6.5 × 104) and the lowest limit of detection (10-7 M). The interaction of linuron with the gold nanocluster was simulated by establishing a simple DFT model which predicted that the most pronounced binding with the gold atom takes place at the benzene ring.

1-Dimensional Selective Nuclear Overhauser Effect NMR Spectroscopy To Characterize Products from a Two-Step Green Chemistry Synthesis

One dimensional (1-D) 1H and 13C NMR experiments are common tools used in undergraduate organic laboratories to characterize synthesized molecules. However, 1-D NMR spectra cannot always provide un...

Interaction between the ionic liquids 1-alkyl-3-methylimidazolium tetrafluoroborate and Pluronic® P103 in aqueous solution: A DLS, SANS and NMR study

The effect of three ionic liquids (ILs) 1-alkyl 3-methyl imidazlolium tetraflouroborates (Cnmim BF4n=4, 6, 8) on micellar solutions of an ethylene oxide-propylene oxide block copolymer (PEO–PPO–PEO), Pluronic® P103 was examined from scattering and NMR techniques. The ILs alter the cloud point and micelle size dependant on their alkyl chain length and the results are discussed in terms of their behavior as cosolvent/cosurfactant. Cloud point data support the hydrogen bonding between the imidazolium cation and P103 while dynamic light scattering (DLS) and small angle neutron scattering (SANS) reveal that presence of ionic liquid is not conducive to the micelle formation of P103. The selective nuclear Overhauser effect (NOESY) indicates that the PPO block of the P103 interacts with the alkyl group of the Cnmim+ cation by hydrophobic interaction. Through this kind of interactions, Cnmim BF4 and P103 can form mixed micelles. This result indicates that the presence of ILs hinders the micelle formation of P103 in solution and promotes P103 to orient at air/water interface.

NMR spectroscopy explained: simplified theory, applications and examples for organic chemistry and structural biology

NMR spectroscopy explained: simplified theory, applications and examples for organic chemistry and structural biology

Effect of Ionic Liquids on the Aggregation Behavior of PEO-PPO-PEO Block Copolymers in Aqueous Solution

Effect of 1-butyl-3-methyl-imidazolium bromide (BmimBr) on the aggregation behavior of PEO-PPO-PEO Pluronic P104 aqueous solution was studied by Fourier transform infrared (FTIR) spectroscopy, freeze fracture transmission electron microscopy (FF-TEM), dynamic light scattering (DLS), and NMR spectroscopy. When the BmimBr concentration was below 1.232 mol/L, the critical micelle temperature (CMT) of Pluronic P104 remained constant, while the size of micelles increased with increasing the BmimBr concentration; above this concentration, the CMT of Pluronic P104 decreased abruptly, and bigger clusters of BmimBr were formed. The selective nuclear Overhauser effect (NOE) spectrum indicates that the PO block of the P104 interacts with the butyl group of the Bmim+ cation by hydrophobic interaction. It suggests that when the concentration of BmimBr is below 1.232 mol/L, there are P104 micelles in the aqueous solution with BmimBr embedding to the micellar core, while above this concentration, P104 micelles and BmimBr clusters coexist in the system.

Revisiting the initial rate approximation in kinetic NOE measurements

The nuclear Overhauser effect (NOE) is undoubtedly one of the most useful tools in NMR spectroscopy and is widely used in solving structural and conformational problems of small organic molecules and macromolecular systems alike. In particular, measurement of the kinetics of the NOE, often facilitated by selective 1D NOE buildup experiments, can generate invaluable quantitative distance information for the molecule being investigated. In practice, analysis of such kinetic NOE data routinely assumes a first-order approximation of the initial buildup rate. However, often times such an approximation holds true only for the shortest mixing times. As shown by Macura and others, the linear range of the NOE buildup obtained from 2D NOESY and exchange experiments can be substantially extended by simply scaling the NOE cross-peaks against the corresponding diagonal peaks. In this note, we demonstrate through a detailed analysis that the same approach can be applied to the analysis of 1D NOE data obtained with the DPFGSE NOE pulse sequence, one of the most widely used selective 1D NOE experiments today. We show that this approach allows the inclusion of data points acquired with much longer mixing times in the analysis and thus considerably improves the accuracy of the measured cross-relaxation rates and internuclear distances, while considerably simplifying the data analysis. Similar results can be obtained for the rotating frame DPFGSE ROE experiment.

Conformational Features of Penicillin G in Solution as Revealed by13C-{1H} Selective Nuclear Overhauser Effects

Abstract 13C-{1H} nuclear Overhauser effects (n.O.e.) were measured for penicillin G in I 2H6 I-DMSO upon selective presaturation of proton resonances and interpreted on the basis of effective correlation times as calculated by analysis of 13C and 1H spin-lattice relaxation rates. Preferential occurrence of a compact C2 puckered conformation with folding of the benzoylamino side chain towards the methyl at C2 was given evidence. A Dreiding model of such conformation was built.

Ansa-Metallocene derivatives : XXV. Synthesis, crystal structure and reactions of a tetramethylethano-bridged vanadocene dichloride, (CH 3) 4C 2(C 5H 4) 2VCl 2

The tetramethylethano-bridged vanadocene complex (CH 3) 4C 2(C 5H 4) 2VCl 2 has been made in two ways: (i) from VCl 3·3THF by reaction with (CH 3) 4C 2(C 5H 4MgCl·2THF) 2 in THF and subsequent oxidation with PCl 3, and (ii) from VCl 4·2THF by reaction with (CH 3) 4C 2(C 5H 4Li) 2 or with (CH 3) 4C 2(C 5H 4MgCl·2THF) 2 in a toluene/dimethoxyethane mixture. Its crystal structure is in accordance with expectations. Reduction of (CH 3) 4C 2(C 5H 4) 2VCl 2 with tetrakis(dimethylamino)ethene in toluene or with LiAlH 4 in THF yields the monochloride (CH 3) 4C 2(C 5H 4) 2VCl; from this V III compound cationic complexes (CH 3) 4C 2(C 5H 4) 2VL 2 + with L = CO or CN tBu are readily obtained by ligand exchange. 1H NMR signals of these diamagnetic complexes have been assigned to H atoms in α and β C 5-ring positions by use of selective nuclear Overhauser effects. The ring-bridged V II complex (CH 3) 4C 2(C 5H 4) 2V could not be prepared. Cyclovoltammetry studies indicate that (in contrast to its unbridged counterpart (C 5H 5) 2V) this V II complex decays within seconds after its formation by electrochemical reduction of its chloro derivatives.

Conformational analysis of methylsulphinyl derivatives of furan and thiophene by employing nuclear magnetic relaxation and lanthanide induced shifts

Relaxation parameters such as nuclear Overhauser effect (NOE) and spin–lattice relaxation times(T1) were applied to the conformational analysis of methylsulphinyl derivatives of furan and thiophene. Correlation times for molecular tumbling, τc, and for methyl reorientation, τi, were obtained. The τi values for the different molecules examined are nearly the same, the τc are twice as large in derivatives that also contain an iodine substituent in the heterocyclic ring. From non-selective, selective and bi-selective T1 measurements and NOE values, relative to 1H nuclei, and a best-fit procedure, the most probable conformational intervals for the methylsulphinyl group were located. Owing to the pyramidal structure of sulphoxides, the preferred conformers could not be fixed unambiguously. From the Lanthanide Induced Shift (LIS) technique on 1H and 13C nuclei, intervals of preferred orientations of the S–O bond with respect to the heterocyclic ring were found. Reliable conclusions about the conformational behaviour of these molecules have been drawn by matching the two sets of results. Relaxation parameters turn out to be useful for conformational analysis of small molecules when employed as a complementary tool with other experimental approaches.

ChemInform Abstract: A Survey of the High‐Field 1H NMR Spectra of the Steroid Hormones, Their Hydroxylated Derivatives, and Related Compounds

1 H NMR chemical shifts are presented for virtually all the protons in 166 steroids. These comprise mainly the hormones testosterone, androst-4-ene-3,17-dione, progesterone, and a wide range of their hydroxylated derivatives, some corticosteroids including aldosterone and a series of its derivatives, together with miscellaneous steroids comprising a variety of androstane and pregnane derivatives, bile acids, and sterols, to provide the first extensive collection of data for use in correlating 1H chemical shifts with structure.Most of the spectra were assigned with the aid of two-dimensional 1H homonuclear correlated spectroscopy (COSY), or in a few cases by use of ω1,-decoupled COSY (COSYDEC) spectroscopy. Limited use was made of other techniques, especially selective nuclear Overhauser effect difference spectroscopy (NOEDS), to complete the more difficult assignments. Procedures for the rapid analysis of high-field 1H NMR spectra of steroids are suggested: they include the application of templates for the recognition of signals due to particular protons from their characteristic profiles, which generally vary only slightly between different steroids unless simplified by adjacent substitution. Substituent increments for all protons are reasonably additive, except where drastic conformational change occurs or adjacent substituents interact strongly. The conformational dependences of hydroxy-substitution increments are analysed empirically, and some regularities are identified.

A monodimensional method for the determination of proton chemical shifts in complex molecular systems based on selective proton-carbon NOE measurements

In the present paper we propose the use of a monodimensional method for proton chemical-shift determination, based on selective proton-carbon nuclear Overhauser effects, {H} C NOE. This method is particularly useful whenever the proton spectrum is tightly coupled, and appears to compete with the two-dimensional experiments

A survey of the high-field 1H NMR spectra of the steroid hormones, their hydroxylated derivatives, and related compounds

1 H NMR chemical shifts are presented for virtually all the protons in 166 steroids. These comprise mainly the hormones testosterone, androst-4-ene-3,17-dione, progesterone, and a wide range of their hydroxylated derivatives, some corticosteroids including aldosterone and a series of its derivatives, together with miscellaneous steroids comprising a variety of androstane and pregnane derivatives, bile acids, and sterols, to provide the first extensive collection of data for use in correlating 1H chemical shifts with structure.Most of the spectra were assigned with the aid of two-dimensional 1H homonuclear correlated spectroscopy (COSY), or in a few cases by use of ω1,-decoupled COSY (COSYDEC) spectroscopy. Limited use was made of other techniques, especially selective nuclear Overhauser effect difference spectroscopy (NOEDS), to complete the more difficult assignments. Procedures for the rapid analysis of high-field 1H NMR spectra of steroids are suggested: they include the application of templates for the recognition of signals due to particular protons from their characteristic profiles, which generally vary only slightly between different steroids unless simplified by adjacent substitution. Substituent increments for all protons are reasonably additive, except where drastic conformational change occurs or adjacent substituents interact strongly. The conformational dependences of hydroxy-substitution increments are analysed empirically, and some regularities are identified.

Selective 1H–13C and 1H–1H nuclear overhauser enhancement studies of adenosine–thymidine interaction in solution

Selective proton–carbon nuclear Overhauser effect (NOE) measurements have been widely used to analyse through-space proton–carbon interactions. Intermolecular interactions between adenosine and thymidine have been studied by means of selective {H}C-NOE spectroscopy. Moreover, the role of proton chemical exchange in determining {H}C-NOE has been considered. A combined use of homo- and hetero-nuclear selective NOE to account the chemical exchange contribution to the experimental {H}C-NOE has been proposed.

Hydrogen exchange of individual amide protons in the F helix of cyanometmyoglobin.

Hydrogen exchange of the individual amide protons of alanine-90 (F5), glutamine-91 (F6), serine-92 (F7), and histidine-93 (F8) residues in cyanometmyoglobin of sperm whale has been studied by 1H nuclear magnetic resonance spectroscopy at 360 MHz. The amide proton resonance of F5, F6, and F7 have been assigned by use of the selective nuclear Overhauser effect between the consecutive amide protons. At pH 6.8, and in the temperature range of 5-20 degrees C, these protons show a 10(4)-fold retardation compared to the rates in free peptides. Apparent activation enthalpies for hydrogen exchange of F5, F6, and F8 protons are 18.5 +/- 0.4, 9.5 +/- 0.3, and 18.5 +/- 0.3 kcal/mol, respectively. Some implications of these results on the nature of the opening processes involved in hydrogen exchange are considered.

Epidermal growth factor from the mouse. Physical evidence for a tiered beta-sheet domain: two-dimensional NMR correlated spectroscopy and nuclear Overhauser experiments on backbone amide protons.

When H2O-exchanged, lyophilized mouse epidermal growth factor (mEGF) is dissolved in deuterium oxide at low pH (i.e., below approximately 6.0), 13 well-resolved, amide proton resonances are observed in the downfield region of an NMR spectrum (500 MHz). Under the conditions of these experiments, the lifetimes of these amide protons in exchange for deuterons of the deuterium oxide solvent suggest that these amide protons are hydrogen-bonded, backbone amide protons. Several of these amide proton resonances show splittings (i.e., JNH alpha-CH) of approximately 8-10 Hz, indicating that their associated amide protons are in some type of beta-structure. Selective nuclear Overhauser effect (NOE) experiments performed on all amide proton resonances strongly suggest that all 13 of these backbone amide protons are part of a single-tiered beta-sheet structural domain in mEGF. Correlation of 2D NMR correlated spectroscopy data, identifying scaler coupled protons, with NOE data, identifying protons close to the irradiated amide protons, allows tentative assignment of some resonances in the NOE difference spectra to specific amino acid residues. These data allow a partial structural model of the tiered beta-sheet domain in mEGF to be postulated.

Solvent and temperature effects on crambin, a hydrophobic protein, as investigated by proton magnetic resonance.

Crambin, a water-insoluble protein of molecular weight 5000, has been studied by 1H-NMR at 270 MHz and 300 MHz as a function of temperature and solvent composition. In (2H4)acetic acid the resonances sharpen up to 75 °C and broaden upon further heating owing to conformational exchange. In (2H7)dimethylformamide, temperature mainly causes monotonic narrowing as a result of high mobility and disaggregation. Crambin, dissolved in acetic acid at 55 °C, dried and redissolved in dimethylformamide, yields a room-temperature spectrum that is considerably narrower than that of the untreated protein dissolved in the same solvent. Acetic acid pretreatment thus interferes with aggregation in dimethylformamide. Both these spectra are closely similar to that of the protein in acetic acid. Given the complementary acid-base nature of acetic acid and dimethylformamide, we conclude that spectra in these two solvents arise from conformations closely related to the native structure. Crambin undergoes extensive unfolding in (2H6)dimethylsulfoxide at 25°C. In contrast, up to 105°C. In contrast, up to 105°C in dimethylformamide and at least up to 85°C in acetic acid the protein structure is only partially altered. These observations substantiate an unprecedented thermal stability for crambin. Proton decoupling experiments are shown that verify vicinal relationships among tyrosyl aromatic resonances. Similar experiments identify a high-field-shifted methyl triplet as arising from an isoleucyl residue. Selective nuclear Overhauser effects are shown that relate this methyl group to a partially constrained tyrosyl ring. This is consistent with the crystallographic model that shows Ile-33 to be in close proximity to Tyr-44.

Interaction of the antimalarial drug fluoroquine with DNA, tRNA, and poly(A): 19F-NMR chemical-shift and relaxation, optical absorption, and fluorescence studies.

AbstractThe interaction of the fluorinated antimalarial drug fluoroquine [7‐fluoro‐4‐(diethyl‐amino‐1‐methylbutylamino)quinoline] with DNA, tRNA, and poly(A) has been investigated by optical absorption, fluorescence, and 19F‐nmr chemical‐shift and relaxation methods. Optical absorption and fluorescence experiments indicate that fluoroquine binds to nucleic acids in a similar manner to that of its well‐known analog chloroquine. At low drug‐to‐base pair ratios, binding of both drugs appears to be random. Fluoroquine and chloroquine also elevate the melting temperature (Tm) of DNA to a comparable extent. Binding of fluoroquine to DNA, tRNA, or poly(A) results in a downfield shift of about 1.5 ppm for the 19F‐nmr resonance. The chemical shift of free fluoroquine depends on the isotopic composition of the solvent (D2O vs H2O). The solvent isotope shift is virtually eliminated by fluoroquine binding to any one of the nucleic acids. 19F‐nmr relaxation experiments were carried out to measure the spin‐lattice relaxation time (T1), 19F{1H} nuclear Overhauser effect (NOE), off‐resonance intensity ratio (R), off‐resonance rotating‐frame spin‐lattice relaxation time (T), and linewidth for fluoroquine in the nucleic acid complexes. By accounting for intramolecular proton‐fluorine dipolar and chemical‐shift anisotropy contributions to the fluorine relaxation, all of the relaxation parameters for the fluoroquine–DNA complex can be well described by a motional model incorporating long‐range DNA bending on the order of a microsecond and an internal motion of the drug on the order of a nanosecond. Selective NOE experiments indicate that the fluorine in the drug is near the ribose protons in the RNA complexes, but not in the DNA complex. Details of the binding evidently differ for the two types of nucleic acids. This study provides the foundation for an investigation of fluoroquine in intact cells.

Relaxation in an A2 coupled spin system dissolved in a perdeuterated liquid crystal: The intermolecular dipolar random field cross relaxation term

A perdeuterated nematic liquid crystal N- (p-ethoxybenzylidene) -p-n-butylaniline (EBBA-d23, 98% deuterium) was synthesized to study relaxation of small molecules dissolved in anisotropic solvents. Proton spin–lattice relaxation in the coupled A2 spin system of methylene chloride (CH2Cl2) was studied using both perhydro and perdeutero EBBA as the solvent. The relaxation was modeled as intramolecular dipole–dipole interactions plus other mechanisms that were treated collectively as fluctuating external random magnetic fields. Comparison of relaxation in EBBA and EBBA-d23 allowed the first experimental measurement of the correlation coefficient between external random fields at the two protons due to dipolar interactions of the methylene protons with the protons or deuterons of the solvent (78% correlated). The selective nuclear Overhauser effect was also studied.