NMR Nuclear Overhauser Effect Research Articles

2S-(1RS-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine

In medicinal chemistry, the precise configuration of molecules is a crucial determinant of their pharmacological properties. Hence, the introduction of a new chiral center during the synthetic pathway involves the assignment of configuration. Herein we assign, by means of molecular modeling 1H and 2D Nuclear Overhauser Effect NMR techniques, the configuration of the two diastereomers 2S-(1R-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine and 2S-(1S-benzyloxy-hex-5-enyl)-2,3-dihydro-1,4-benzodioxine, which are useful to synthetize analogs of the potent and highly selective dipeptidyl peptidase IV and carbonic anhydrase inhibitor recently published.

Insights into dynamic properties of water in lipidic cubic phases by 2D nuclear Overhauser effect (NOE) NMR spectroscopy

Two-dimensional NOE (nuclear Overhauser effect) NMR spectroscopy was employed to investigate the dynamic properties of water within lyotropic bicontinuous lipidic cubic phases (LCPs) formed by monoolein (MO). Experiments observed categorically different effective residence times of water molecules: (i) in proximity to the glycerol moiety of MO, and (ii) adjacent to the hydrophobic chain towards the hydrocarbon tail of MO, as evidenced by the opposite signs of intermolecular NOE cross peaks between protons of water and those of MO in 2D 1H–1H NOESY spectra. Spectroscopic data delineating the different effective residence times of water molecules within both the gyroid (QIIG) and diamond (QIID) phase groups corresponding to hydration levels of 35 and 40 wt%, respectively, are presented. Additionally, an increase in effective residence time of water molecules in proximity to the glycerol moiety of MO in LCPs was observed upon storage at ambient temperature and in the presence of an additive lipid, cholesterol. Atom-specific NOE build-up curves for protons of water and those of MO are also given. The results presented herein provide new insight into the physicochemical properties and behaviour of water in LCPs, and demonstrate an additional avenue for experimental study of water–lipid interactions and hydration dynamics in model membranes and nanomaterials using 2D NOE NMR spectroscopy.

Ring Expansion Alkyne Metathesis Polymerization.

The synthesis, characterization, and preliminary activity of an unprecedented tethered alkylidyne tungsten complex for ring expansion alkyne metathesis polymerization (REAMP) are reported. The tethered alkylidyne 7 is generated rapidly by combining alkylidyne W(CtBu)(CH2tBu)(O-2,6-i-Pr2C6H3)2 (6) with 1 equiv of an yne-ol proligand (5). Characterized by NMR studies and nuclear Overhauser effect spectroscopy, complex 7 is a dimer. Each metal center contains a tungsten-carbon triple bond tethered to the metal center via an alkoxide ligand. The polymerization of the strained cycloalkyne 3,8-didodecyloxy-5,6-dihydro-11,12-didehydrodibenzo[a,e]-[8]annulene, 8, to generate cyclic polymers was demonstrated. Size exclusion chromatography (SEC) and intrinsic viscosity (η) measurements confirm the polymer's cyclic topology.

Ion clustering, aggregation and diffusion in amide based deep eutectic solvents: A microstructural investigation using various NMR spectroscopic techniques and molecular dynamics simulation

A thorough understanding of the structure and dynamics of deep eutectic solvents (DESs) is necessary to optimize the uses of this new class of solvents for many potential applications. Herein, we have studied ion clustering, aggregation and diffusion mechanism in DESs composed of acetamide and sodium/potassium thiocyanate using 1D NMR, pulsed field gradient stimulated echo (PFGSE) NMR and 2D nuclear Overhauser effect spectroscopy (2D NOESY) techniques, and molecular dynamics simulation. We have varied the fraction of salts to investigate the composition dependent microscopic structural insight. A great enhancement in diffusion coefficient (D) of acetamide with increasing the fraction of KSCN (fKSCN) has been observed in PFGSE measurements. The experimental diffusion activation energy (Ea) decreases significantly with increasing fKSCN, which is in excellent agreement with the Ea values obtained from simulated mean squared displacements (MSD). The calculated radial distribution functions (RDF) indicate that the Na+ ions strongly coordinate with acetamide molecules and form ion-clusters and aggregated structures in the medium. However, as Na+ ions are gradually replaced by K+ ions, ion-clustering and aggregation decrease due to relatively weak coordination ability of larger cation, which supports the enhancement of experimental D with increasing fKSCN. In the 2D NOESY study, the intensity of the cross peaks between methyl and amide protons of acetamide decreases relative to the diagonal peak intensity as the fKSCN increases in the medium. This study indicates that the extent of intermolecular NOE reduces as the structural flexibility increases due to less efficient ion-clustering with increasing K+ ion concentration, thus strongly corroborates the results from PFGSE experiment and simulation. Furthermore, 1D and 2D NMR data exhibit an intramolecular chemical exchange between two amide protons in acetamide, the extent of which increases with increasing temperature as well as fKSCN in the DES system. The present study provides a multifaceted picture of composition-dependent distinct microstructures in DES.

Ligands on Nanocrystal Surfaces, the 1H Nuclear Magnetic Resonance Fingerprint.

ConspectusSurfaces are an integral part of colloidal nanocrystals (NCs). Hence, understanding the binding and packing to NC surfaces of organic ligands, which are often used to stabilize NC colloids, is an essential aspect of the formation of NCs with desired chemical or physical properties. Since NCs lack a unique structure, not a single analytical technique can provide a complete description of the chemistry of NC surfaces. Even so, solution 1H nuclear magnetic resonance spectroscopy stands out as a unique method to study the organic ligand shell for its capability to distinguish between surface bound species and surface inactive residues from NC synthesis and purification.In this account, we first set the stage by highlighting the fingerprints of ligands bound to NCs in solution 1H NMR, which are broadened and shifted resonances, slow diffusion, and pronounced transfer of spin polarization between nearby protons. These characteristics enable bound ligands to be identified and quantified by 1D 1H NMR spectroscopy, diffusion-ordered spectroscopy (DOSY), and nuclear Overhauser effect spectroscopy (NOESY). Even so, we argue in a second part that much more insight in surface chemistry can be obtained from the in situ monitoring of ligand exchange processes. The chemical analysis of released compounds and the thermodynamic study of exchange equilibria provide a surprisingly detailed picture of the chemistry of the NC-ligand bond, the heterogeneity of binding sites, and the bunching of ligands on the NC surface. Multiple case studies are discussed to illustrate these different aspects of NC surface chemistry, where work on CdSe NCs in particular indicates that binding sites at facet edges are most vulnerable for ligand loss. While such weak binding sites are a liability for optoelectronic applications, they could offer an opportunity for catalysis. Moreover, the general character of the methodology introduced calls for realizing a broad, quantitative survey of NC-ligand interactions, well beyond the extensively studied case of CdSe NCs.In a third part, we address in more detail the line broadening that characterizes ligands bound to NCs, which results from a combination of reduced mobility and a diversity of chemical environments. Hence, chemical shift and line shape, or rates of transversal relaxation and interligand cross-relaxation, can all convey information on the ligand environment, especially when solvents are used that are chemically distinct from the ligand chain, such as aromatic versus aliphatic. Two examples that illustrate this point are the relation between line width and ligand solvation, where better solvated ligands yield more narrow resonances, and the possibility to identify different parts of the inhomogeneously broadened resonance with ligands bound on different locations at the NC surface. Interestingly, such results question the limits of NC size and ligand packing density at which the current bound-ligand paradigm, modest inhomogeneous broadening, will break down. Building on this question, we summarize in a final part the current status of NC ligand analysis by solution 1H NMR and outline directions for further research.

Unusual Cation-Pi Solute Interactions with Deep Eutectic Solvents

Deep eutectic solvents (DESs) have emerged as an alternative to both common organic solvents and ionic liquids (ILs). DESs share physicochemical properties with ILs such as low vapor pressure, high thermal stability, high viscosity while offering advantages such as low toxicity, lower cost, and ease of preparation. Moreover, DESs are attractive candidates for electrochemical applications due to their large voltage windows and solubility properties. DESs as a solvent class share a general composition of a hydrogen bond donor (HBD), typically a polyol, amide, or acid, and a hydrogen box acceptor (HBA), usually a quaternary ammonium or phosphonium salt. At a specific molar composition of a HBD and HBD, the DES forms a eutectic mixture resulting in a large melting point depression due to extensive hydrogen bonding between the components.Despite being widely studied, the use and subsequent characterization of DESs as solvents for aromatic phenols and related aromatics has only recently received attention. In this study we have investigated the solubility of a broad class of aromatic solutes as a function of DES composition and solute concentration using 1H, 13C, pulsed field gradient (PFG), and nuclear Overhauser effect (NOE) NMR. The degree to which homogenous mixtures versus heterogeneous and/or multi-phase systems are formed as a function of solute, temperature, and DES composition is examined. Two classes of DESs glyceline (glycerol + choline chloride) and ethaline (ethylene glycol + choline chloride) were investigated.As many as three distinct phases depending on the nature of the aromatic solute are observed by NMR. {1H-1H}-NOESY measurements show strong correlations between the choline chloride ammonium cation and the aryl protons with cation-pi interactions disrupting the hydrogen bonding network of the DES. We will discuss the implications for these systems as green solvents and comment on how clustering of solutes on the nanoscale may find use in catalysis and self-assembly.

Double Tethered Metallacyclobutane Catalyst for Cyclic Polymer Synthesis.

This work outlines an approach to creating a catalyst for cyclic polymer synthesis using readily available materials in only one or two steps. Combining commercially available molybdenum-alkylidene 1 with two equivalents of ene-ol proligand 2 rapidly produces, in quantitative yield (1H NMR spectroscopy), the double tethered metallacyclobutane complex 3. Characterized by variable temperature NMR studies and nuclear Overhauser effect spectroscopy (NOESY) experiments, complex 3 exhibits fluxional behavior in solution. Determined by single crystal X-ray diffraction, the solid-state structure of complex 3 reveals metrical parameters indicating that the metallacyclobutane is not predicted to undergo rapid retro-cycloaddition. However, complex 3 is a precatalyst for the polymerization of norbornene to produce cyclic polynorbornene. An NMR spectrum of a test polymerization indicates that only a small fraction of the precatalyst is activated upon exposure to monomer. Quantifying the active catalyst is possible by measuring vinyl resonances that appear in the 1H NMR spectrum. The vinyl resonances are attributable to the release of one of the tethers upon norbornene addition. Confirmation of the polymer cyclic topology comes from gel permeation chromatography (GPC), dynamic light scattering (DLS), and intrinsic viscosity (η) measurements. The double tethered metallacyclobutane complex is a novel design for catalytic cyclic polymer synthesis. The synthetic approach suggests that catalyst tuning is possible by a choice of the commercial alkylidene and alteration of the ene-ol proligand.

Controlling the Chain Folding for the Synthesis of Single-Chain Polymer Nanoparticles Using Thermoresponsive Polymers

Synthetic polymer single-chain nanoparticles (SCNPs) are an emerging new class of nanomaterials that possess similar folded structures as natural proteins. However, most SCNPs reported so far are p...

Anion Binding Affinity: Acidity versus Conformational Effects.

High-level quantum chemical calculations were used to elucidate the gas- and solution-phase conformational equilibria for a series of symmetrically substituted (thio)ureas, (thio)squaramides, and croconamides. Gas-phase calculations predict that the thermodynamic conformer of many of these anion receptors is not the dual-hydrogen-bond-facilitating anti-anti conformer as is commonly assumed. For N,N'-diaryl thiosquaramides and croconamides, the syn-syn conformer is typically the predominant conformer. Solution-phase calculations show that the anti-anti conformer is increasingly stabilized as the polarity of the solvent increases. However, the syn-syn conformer remains the lowest energy conformation for croconamides. These predictions are used to explain the acidity versus chloride binding affinity correlations recently reported for some of these compounds. The chloride binding constants for thioureas and croconamides are significantly lower than expected on the basis of their pKa values, and this may be due in part to the need for these receptors to reorganize into the anti-anti conformer. Experimental NMR nuclear Overhauser effect (NOE) measurements of an asymmetrically substituted squaramide and its thio analogue are consistent with the syn-syn conformation being predominant at 298 K. The conformational equilibria should therefore be an important consideration for the design and development of future anion receptors and organocatalysts.

Interpreting In Vitro Release Performance from Long-Acting Parenteral Nanosuspensions Using USP-4 Dissolution and Spectroscopic Techniques.

Injectable sustained release dosage forms have emerged as desirable therapeutic routes for patients that require life-long treatments. The prevalence of drug molecules with low aqueous solubility and bioavailability has added momentum toward the development of suspension-based long-acting parenteral (LAP) formulations; the previously undesirable physicochemical properties of Biopharmaceutics Classification System (BCS) Class II/IV compounds are best suited for extended release applications. Effective in vitro release (IVR) testing of crystalline suspensions affirms product quality during early-stage development and provides connections with in vivo performance. However, before in vitro-in vivo correlations (IVIVCs) can be established, it is necessary to evaluate formulation attributes that directly affect IVR properties. In this work, a series of crystalline LAP nanosuspensions were formulated with different stabilizing polymers and applied to a continuous flow-through (USP-4) dissolution method. This technique confirmed the role of salt effects on the stability of polymer-coated nanoparticles through the detection of disparate active pharmaceutical ingredient (API) release profiles. The polymer stabilizers with extended hydrophilic chains exhibited elevated intrapolymer activity from the loss of hydrogen-bond cushioning in dissolution media with heightened ionic strength, confirmed through one-dimensional (1D) 1H NMR and two-dimensional nuclear Overhauser effect spectroscopy (2D NOESY) experiments. Thus, steric repulsion within the affected nanosuspensions was limited and release rates decreased. Additionally, the strength of interaction between hydrophobic polymer components and the API crystalline surface contributed to suspension dissolution properties, confirmed through solution- and solid-state spectroscopic analyses. This study provides a unique perspective on the dynamic interface between the crystalline drug and aqueous microenvironment during dissolution.

Burkholderia cenocepacia H111 Produces a Water-Insoluble Exopolysaccharide in Biofilm: Structural Determination and Molecular Modelling.

Biofilms are a multicellular way of life, where bacterial cells are close together and embedded in a hydrated macromolecular matrix which offers a number of advantages to the cells. Extracellular polysaccharides play an important role in matrix setup and maintenance. A water-insoluble polysaccharide was isolated and purified from the biofilm produced by Burkholderia cenocepacia strain H111, a cystic fibrosis pathogen. Its composition and glycosidic linkages were determined using Gas–Liquid Chromatography–Mass Spectrometry (GLC–MS) on appropriate carbohydrate derivatives while its complete structure was unraveled by 1D and 2D NMR spectroscopy in deuterated sodium hydroxide (NaOD) aqueous solutions. All the collected data demonstrated the following repeating unit for the water-insoluble B. cenocepacia biofilm polysaccharide: [3)-α-d-Galp-(1→3)-α-d-Glcp-(1→3)-α-d-Galp-(1→3)-α-d-Manp-(1→]n Molecular modelling was used, coupled with NMR Nuclear Overhauser Effect (NOE) data, to obtain information about local structural motifs which could give hints about the polysaccharide insolubility. Both modelling and NMR data pointed at restricted dynamics of local conformations which were ascribed to the presence of inter-residue hydrogen bonds and to steric restrictions. In addition, the good correlation between NOE data and calculated interatomic distances by molecular dynamics simulations validated potential energy functions used for calculations.

Investigation on the Epoxidation of Piperitenone, and Structure-activity Relationships of Piperitenone Oxide for Differentiation-inducing Activity.

Piperitenone oxide, a major chemical constituent of the essential oil of spearmint, Mentha spicata, induces differentiation in human colon cancer RCM-1 cells. In this study, piperitenone oxide and trans-piperitenone dioxide were prepared as racemic forms by epoxidation of piperitenone. The relative configuration between two epoxides in piperitenone dioxide was determined to be trans by 1H NMR analysis and nuclear Overhauser effect spectroscopy (NOESY) in conjunction with density functional theory (DFT) calculations. Optical resolution of (±)-piperitenone oxide by high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) afforded both enantiomers with over 98% enantiomeric excess (ee). Evaluation of the differentiation-inducing activity of the synthetic compounds revealed that the epoxide at C-1 and C-6 in piperitenone oxide is important for the activity, and (+)-piperitenone oxide has stronger activity than (-)-piperitenone oxide. The results obtained in this study provide new information on the application of piperitenone oxide and spearmint for differentiation-inducing therapy. Furthermore, natural piperitenone oxide was isolated from M. spicata. The enantiomeric excess of the isolated natural piperitenone oxide was 66% ee. Epoxidation of piperitenone with hydrogen peroxide proceeded in a phosphate buffer under weak basic conditions to give (±)-piperitenone oxide. These results suggest that the nonenzymatic epoxidation of piperitenone, which causes a decrease in the enantiomeric excess of natural piperitenone oxide, is accompanied by an enzymatic epoxidation in the biosynthesis of piperitenone oxide.

Structure of micelle bound cationic peptides by NMR spectroscopy using a lanthanide shift reagent.

[Tm(DPA)3]3- was used to generate multiple, paramagnetic nuclear Overhauser effect NMR spectra of cationic peptides when weakly bound to a lipopolysaccharide micelle. Increased spectral resolution combined with a marked increase in the number of distance restraints yielded high resolution structures of polymyxin and MSI-594 in the liposaccharide bound state.

Recognition Selectivities of Lasso-Type Pseudo[1]rotaxane Based on a Mono-Ester-Functionalized Pillar[5]arene.

Two types of mono-ester-functionalized pillar[5]arenes, P1 and P2, bearing different side-chain groups, were synthesized. Their host–guest complexation and self-inclusion properties were studied by 1H NMR and 2D nuclear overhauser effect spectroscopy (NOESY) NMR measurements. The results showed that the substituents on their phenolic units have a great influence on the self-assembly of both pillar[5]arenes, although they both could form stable pseudo[1]rotaxanes at room temperature. When eight bulky 4-brombutyloxy groups were capped on the cavity, instead of methoxy groups, pseudo[1]rotaxane P1 became less stable and its locked ester group in the inner space of cavity was not as deep as P2, leading to distinctly different host–guest properties between P1 and P2 with 1,6-dibromohexane. Moreover, pillar[5]arene P1 displayed effective molecular recognition toward 1,6-dichlorohexane and 1,2-bromoethane among the guest dihalides. In addition, the self-complex models and stabilities between P1 and P2 were also studied by computational modeling and experimental calculations.

Photoresponsive Behavior of Wormlike Micelles Constructed by Gemini Surfactant 12-3-12·2Br- and Different Cinnamate Derivatives.

The photoresponsive wormlike micelles constructed by Gemini surfactants and cinnamate derivatives play a great role in the field of smart materials. However, how the structure of cinnamate derivatives affects the photoresponsive behavior of micelles is still a hotspot for scientists to research. Here, three kinds of aromatic salts with different ortho-substituted groups including trans- o-methoxy cinnamate ( trans-OMCA), trans- o-hydroxy cinnamate ( trans-OHCA), and trans-cinnamate ( trans-CA) were introduced into Gemini surfactant 12-3-12·2Br- aqueous solutions to construct photoresponsive wormlike micelles through their noncovalent interactions. Their properties were researched using the rheological method, cryo-transmission electron microscopy, and 1H NMR and two-dimensional nuclear Overhauser effect spectra. The results show that these cinnamate derivatives could well construct wormlike micelles with 12-3-12·2Br-. Furthermore, subtle differences in the ortho substituents' structure have a significant effect on the photoresponsive behavior of formed wormlike micelles. Specifically, the zero viscosity (η0) of 40 mM 12-3-12·2Br-/24 mM trans-OHCA mixed solution decreases from 26.72 to 2.6 Pa·s with the shortening of the length of wormlike micelles after UV irradiation. Correspondingly, the η0 for the same ratio of 12-3-12·2Br-/ trans-OMCA decreases from 2.42 to 0.06 Pa·s and the wormlike micelles are transited into rodlike micelles and even spherical micelles after the same UV irradiation time. However, the variation of wormlike micelles in the 12-3-12·2Br-/ trans-CA system induced by UV light is not obvious with η0 being maintained at around 2.89 Pa·s. This study will help us better understand the effects of chemical groups on macrophenomena and microinteraction for micellar systems. It provides a theoretical basis for the construction of photoresponsive micelles, thus widening their application in the field of soft materials.

Improved transdermal permeability of ibuprofen by ionic liquid technology: Correlation between counterion structure and the physicochemical and biological properties

The aim of this study was to explore the feasibility of transdermal delivery of ibuprofen using ionic liquid technology. Ibuprofen, a non-steroidal anti-inflammatory drug, was transformed into nine ionic liquids using aromatic, tetraalkylammonium and tetraalkylphosphonium cationic counterions. Both the free drug and synthesized ionic liquids were fully characterized by X-ray Powder Diffractometry (XRPD) analysis, thermal analysis, Fourier Transform Infrared Spectroscopy (FT-IR) analysis and Nuclear Magnetic Resonance Spectrometer analysis (NMR), and the aqueous solubility at 25 °C as well as the octanol-water partition coefficients (LogP) were measured. To evaluate transdermal potential, in vitro skin permeation testing was carried out via Skin Parallel Artificial Membrane Permeability Assays (Skin PAMPA). In addition, the potential skin toxicity of ionic liquids was evaluated by determining their cytotoxicity against HaCaT cells. All the synthesized ibuprofen ionic liquids showed improved skin permeability comparing with the conventional sodium salt. Specifically, ionic liquids with didecyldimethylammonium and tetrahexylammonium counterions were significantly more permeable through artificial skin membrane than the free form of ibuprofen. Conductivity test and 2D NMR nuclear Overhauser effect (NOE) techniques corroborated that ionic liquids with stronger intermolecular intermolecular interaction and higher degree of ion association in aqueous environment crossed the artificial skin membrane more rapidly and efficiently. Taken together, ionic liquids technology could be a versatile platform to turn the physicochemical and biological properties of ionizable drugs and facilitate their transdermal delivery.

Unprecedented Large Hyperpolarizability of Twisted Chromophores in Polar Media.

Twisted intramolecular charge transfer (TICT) chromophores exhibit uniquely large second-order optical nonlinearities ( μβ). However, their promise as electro-optic (E-O) materials is yet untapped, reflecting a strong tendency to aggregate in low-polarity media, leading to a dramatic fall in μβ. Until now, TICT chromophores in deaggregating polar solvents suffered decreased response due to polarity-driven changes in electronic structure. Here we report a new series of benzimidazolium-based TICT chromophores with interaryl torsional angles in the range of 64-77°. The most twisted, B2TMC-2, exhibits a large μβvec = -26,000 × 10-48 esu (at 1907 nm) in dilute nonpolar CH2Cl2 solution, which is maintained in polar DMF ( μβvec= -20,370 × 10-48 esu) as measured by DC electric field-induced second harmonic generation (EFISH). Sterically enforced interaryl torsional angles are confirmed by single-crystal X-ray diffraction and solution phase Nuclear Overhauser Effect (NOE) NMR, and spectroscopic characterization reveals a zwitterionic/aromatic ground state electronic structure associated with the high μβ. We show that increasingly disrupted conjugation is correlated with increased μβ even at intermediate twist angles. The excellent performance and reduced aggregation in polar solvents opens new avenues for bridging microscopic and macroscopic chromophore performance.

Interaction of Tyrosine Analogues with Quaternary Ammonium Head Groups at the Micelle/Water Interface and Contrasting Effect of Molecular Folding on the Hydrophobic Outcome and End-Cap Geometry.

The surface property of the cationic micelles of cetyltrimethylammonium bromide (CTAB) in an aqueous medium is highly modified in the presence of tyrosineoctyl ester (TYOE) and tyrosinedodecyl ester (TYDE), the models for aromatic amino acid side chains of transmembrane proteins. While the synergistic interaction between the quaternary ammonium head group of CTAB and the π-electron cloud of aromatic amino acid ester is influenced by the relative orientation and the unusual molecular geometry of the latter, this eventually triggers a morphology transition of the spherical micelle to cylindrical/wormlike micelles and imparts a strong viscoelasticity in the medium. Physical characteristics of the elongated micelles have been investigated by high resolution transmission electron microscopy (HRTEM) and the small angle neutron scattering (SANS) technique; the complex fluidic nature of the system is investigated by a dynamic rheological measurement. The intermolecular interactions have been recognized via 1H NMR and 2D nuclear Overhauser effect spectroscopy (NOESY), and the unambiguous geometry of the end-caps of the rods has been ascertained for the first time. While the interplay between lipids and transmembrane proteins is thought to be crucial in controlling the membrane shape of the cells during many vital events such as cellular fission, fusion, and virus entry, the observed tuning of the micellar surface curvature via the cation-π interaction involving tyrosine analogues is thought provoking and opens up an avenue for new physical chemistry research on a vital biological phenomena.

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...

15N-Labelling and structure determination of adamantylated azolo-azines in solution.

Determining the accurate chemical structures of synthesized compounds is essential for biomedical studies and computer-assisted drug design. The unequivocal determination of N-adamantylation or N-arylation site(s) in nitrogen-rich heterocycles, characterized by a low density of hydrogen atoms, using NMR methods at natural isotopic abundance is difficult. In these compounds, the heterocyclic moiety is covalently attached to the carbon atom of the substituent group that has no bound hydrogen atoms, and the connection between the two moieties of the compound cannot always be established via conventional 1H-1H and 1H-13C NMR correlation experiments (COSY and HMBC, respectively) or nuclear Overhauser effect spectroscopy (NOESY or ROESY). The selective incorporation of 15N-labelled atoms in different positions of the heterocyclic core allowed for the use of 1H-15N (JHN) and 13C-15N (JCN) coupling constants for the structure determinations of N-alkylated nitrogen-containing heterocycles in solution. This method was tested on the N-adamantylated products in a series of azolo-1,2,4-triazines and 1,2,4-triazolo[1,5-a]pyrimidine. The syntheses of adamantylated azolo-azines were based on the interactions of azolo-azines and 1-adamatanol in TFA solution. For azolo-1,2,4-triazinones, the formation of mixtures of N-adamantyl derivatives was observed. The JHN and JCN values were measured using amplitude-modulated 1D 1H spin-echo experiments with the selective inversion of the 15N nuclei and line-shape analysis in the 1D 13С spectra acquired with selective 15N decoupling, respectively. Additional spin–spin interactions were detected in the 15N-HMBC spectra. NMR data and DFT (density functional theory) calculations permitted to suggest a possible mechanism of isomerization for the adamantylated products of the azolo-1,2,4-triazines. The combined analysis of the JHN and JCN couplings in 15N-labelled compounds provides an efficient method for the structure determination of N-alkylated azolo-azines even in the case of isomer formation. The isomerization of adamantylated tetrazolo[1,5-b][1,2,4]triazin-7-ones in acidic conditions occurs through the formation of the adamantyl cation.