Sp2 Nitrogen Research Articles

Nitrogen implantation of suspended graphene flakes: Annealing effects and selectivity of sp2 nitrogen species

Nitrogen inclusion in both chemical vapour deposition and exfoliated few-layer graphene flakes was performed by nitrogen ion implantation in ultra-high vacuum. Inclusion of up to ∼20 at.% nitrogen can be reached through this clean technique with absence of oxygen species in the final product, while maintaining a largely sp2-carbon network. The nitrogen inclusion was observed by scanning X-ray photoelectron microscopy (SPEM) with energy resolution of 0.2eV and spatial resolution of 10nm. SPEM can be used to follow the evolution of nitrogen species: pyridinic, graphitic, and pyrrolic, at different doping stages and annealing temperatures. Variations in the ratio between sp2 nitrogen species was observed for increasing treatment time; annealing results in quenching of the sp3 component, suggesting the graphitic nitrogen as the most thermal stable species. The occurrence of graphitic species together with the absence of pyrrolic is indicative of N-incorporation into a hexagonal graphene-based lattice. Ion irradiation followed by annealing performed in a controlled way is a promising strategy to fine control the nature of the nitrogen species grafted to the graphene while focusing on selected applications.

Polymer-based biocompatible fluorescent sensor for nano-molar detection of Zn2+ in aqueous medium and biological samples

Chemosensors are prepared through condensation reactions between polymeric amines and three different aldehydes; the activities of the three products were evaluated in DMF–H2O (7 : 3, v/v) solvent system. Chemosensor 2c demonstrated selectivity for Zn2+ enhancement of the fluorescence intensity at 420 nm. Upon binding of 2c with Zn2+, an approximately 9 fold enhancement in fluorescence intensity was observed due to the combined effect of ESIPT, CN isomerisation and the two-channel quenching of PET. The investigation of the photophysical properties of 2c revealed that the sensor at low pH led to a shift in the emission profile because of the presence of two types of nitrogen i.e. sp2 and sp3 nitrogens and the pH dependent fluorescence profile is due to the protonation at sp3 hybridised nitrogen that influences the charge transfer transitions of 2c. However, the salt effect has not much influence on the photophysical properties of 2c; and 2c was found to form organic nano-particles (ONP) in a DMF–H2O (1 : 99, v/v) solvent system and this material was found to detect a minimum of 40 nM concentration of Zn2+. The receptor 2c was found to be biocompatible through MTT assay and potent to detect Zn2+ in real biological conditions of microbial cells. The compounds 2a, 2b and 2c while immobilized in PVC based membrane, exhibited their selectivity for zinc ions as ion selective electrodes. These electrodes responded linearly in a wide concentration range with a lower detection limit of 10 μM. The electrodes have been successfully used as indicator electrodes in potentiometric titration of zinc ions with EDTA.

Imine-linked chemosensors for the detection of Zn2+ in biological samples

A chemosensor 1 with a long hydrocarbon chain and polar end group is synthesized by the simple condensation reaction of a long chain amine with salicylaldehyde. A long chain hydrocarbon with a polar end group is used because of its solubility in an aqueous surfactant solution, which ensures that it can be used in a neutral water medium. The rationale for choosing an aryl aldehyde with –OH functionality is based upon the fact that a chelate ring consisting of an –OH group and an sp2 nitrogen donor is always better for the selective recognition of Zn2+. The sensor shows selective binding to Zn2+ in 1% Triton-X-100 solution. Binding of Zn2+ by sensor 3 leads to an approximately 300% enhancement in the fluorescence intensity of the sensor, due to the combined effects of excited state intramolecular proton transfer (ESIPT) and the inhibition of the photo-induced electron transfer (PET) process by the –OH group. The fluorescence emission profiles of sensor 1 show some changes in the low and high pH ranges, however the sensor remains stable in the pH range 4–9, which makes it appropriate for use in biological fluids.

Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp2 hybridization in the urea as well as a high barrier for sp3 nitrogen inter-conversion, both of which may interfere with recognition by taste receptors.

A fingerprint pair analysis of hERG inhibition data

BackgroundDrugs that bind to the human Ether-a-go-go Related Gene (hERG) potassium channel and block its ion conduction can lead to Torsade de Pointes (TdP), a fatal ventricular arrhythmia. Thus, compounds are screened for hERG inhibition in the drug development process; those found to be active face a difficult road to approval. Knowing which structural transformations reduce hERG binding would be helpful in the lead optimization phase of drug discovery.ResultsTo identify such transformations, we carried out a comprehensive analysis of all approximately 33,000 compound pairs in the Novartis internal database which have IC50 values in the dofetilide displacement assay. Most molecular transformations have only a single example in the data set; however, a few dozen transformations have sufficient numbers for statistical analysis.ConclusionsWe observe that transformations which increased polarity (for example adding an oxygen, or an sp2 nitrogen), decreased lipophilicity (removing carbons), or decreased positive charge consistently reduced hERG inhibition between 3- and 10-fold. The largest observed reduction in hERG was from a transformation from imidazole to methyl tetrazole. We also observe that some changes in aromatic ring substituents (for example hydrogen to methoxy) can also reduce hERG binding in vitro.

How to Make the σ0π2 Singlet the Ground State of Carbenes

Successful strategies have previously been developed to stabilize the σ(2)π(0) singlet states of carbenes, relative to σ(1)π(1) triplet states. However, little or no attention has been paid to the stabilization of the σ(0)π(2) singlet states. We present two simple strategies to stabilize the σ(0)π(2) singlet states of carbenes, relative to both the σ(2)π(0) singlet and σ(1)π(1) triplet states. These strategies consist of destabilization of the carbene σ orbital by two, adjacent, sp(2) nitrogen lone pairs of electrons and stabilization of the carbene 2p-π orbital by incorporating it into a five-membered ring, containing two double bonds, or into a six-membered ring, containing two double bonds and a sixth atom that has a low-lying empty π orbital. B3LYP, CASPT2, and CCSD(T) calculations have been performed in order to assess the success of these strategies in creating derivatives of cyclopenta-2,4-dienylidene and cyclohexa-2,5-dienylidene with σ(0)π(6) singlet ground states. Differences between the calculated geometries and binding energies of the Xe complexes of the σ(0)π(6) singlet ground state of 2,5-diazacyclopentadienylidene (5) and the σ(2)π(0) singlet states of CH2 and CF2 are discussed.

Synthesis and spectroscopic analysis of substituted 2-aminothiazolines

2-Aminothiazolines can exist in two tautomeric species, amino and imino forms, which can theoretically exist as two stereoisomers. Several methods and techniques have been used to evaluate tautomeric process, but in this case 15N NMR spectroscopy was used due to tautomeric process involves two nitrogen atoms. In this paper, we present the synthesis and a HMBC 1H-15N study of four 2-substituted aminothiazolines. It was observed from HMBC contour plot correlation between five membered ring CH2 groups with sp2 nitrogen around 250ppm, while aliphatic hydrogen correlates with sp3 nitrogen around 90ppm, suggesting that amino form is the major or the unique tautomer present in solution. Theoretical calculations at the M06-2X/cc-pVDZ level were performed and indicated that amino tautomer is slightly more stable (∼1kcalmol−1) than imino one.

Interaction of multimicrobial synthetic inhibitor 1,2-bis(2-benzimidazolyl)-1,2-ethanediol with serum albumin: spectroscopic and computational studies.

The molecule, 1,2-Bis(2-benzimidazolyl)-1,2-ethanediol (BBE) is known to act as a selective inhibitor of poliovirus, rhinovirus, Candida albicans, several bacterial species, and is easily synthesized by Phillips reaction. The interaction of BBE with BSA and the effects of its binding on the conformation and unfolding/refolding pathways of the protein were investigated using multispectroscopic techniques and molecular modeling. The binding studies indicate that BSA has one high affinity BBE binding site with association constant 6.02±0.05×104 M−1 at 298 K. By measuring binding at different temperatures, we determined the changes in enthalpy (ΔH = −15.13±2.15 kJ mol−1), entropy (ΔS = 40.87±7.25 J mol−1 K−1) and free energy (ΔG = 26.78±1.02) of interaction, which indicate that the binding was spontaneous and both enthalpically and entropically driven. Based on molecular modeling and thermodynamic parameters, we proposed that the complex formation involved mainly hydrophilic interaction such as hydrogen bonding between hydroxyl groups of ethane-1,2-diol fragment with Tyr410 and benzimidazole sp2 nitrogen atom with Ser488 and hydrophobic interaction between phenyl ring of one benzimidazole of the ligand and hydrophobic residues namely, Ile387, Cys391, Phe402, Val432 and Cys437. The sequential unfolding mechanism of BSA, site-specific marker displacement experiments and molecular modeling showed that the molecule preferably binds in subdomain IIIA. The BBE binding to BSA was found to cause both secondary and tertiary structural alterations in the protein as studied by intrinsic fluorescence, near-UV and far-UV circular dichroism results. The unfolding/refolding study showed that BBE stabilized native to intermediate states (NI) transition of the protein by ∼2 kJ mol−1 without affecting the intermediate to unfolded states (IU) transition and general mechanism of unfolding of BSA.

Computational Studies of the Properties of Azole·xBH3 Adducts for Chemical Hydrogen Storage Systems

The thermodynamic properties of the potential hydrogen storage compounds, the borane adducts of pyrrole, pyrazole, imidazole, triazole, and tetrazole, were calculated at the G3MP2 level by using an isodesmic approach including experimental and accurate (CCSD(T)/CBS) values for the other components of the reaction. The heats of formation, bond dissociation energies, dehydrogenation energies, proton affinities, gas phase acidities, pKas in aqueous solution, and hydride affinities were calculated. The H3B–N dative bonds to an sp2 nitrogen are much stronger than those to an sp3 nitrogen for the 5-member rings. The dehydrogenation energies at the sp3 nitrogen for the azole borane adducts are exothermic and those at the sp2 nitrogen borane adducts are closer to thermoneutral (−7.7 to +9.4 kcal/mol). The gas phase acidity decreases (becomes more acidic) with increasing the number of the nitrogen atoms in the 5-member heterocycle and with increasing the number of coordinated BH3 molecules to the azole nitrogens. ...

Synthesis, electrochemistry, and photophysical properties of pyrazolino[60]fullerene–1,8-naphthalimide fluorescent derivatives

A series of pyrazolino[60]fullerene–1,8-naphthalimide (Pz[60]–NI) fluorescent derivatives were synthesized in one pot by a [3+2] dipolar cycloaddition between C60 and functionalized hydrazones in good yield. In contrast with 4-aziridino[60]fullerene–1,8-naphtalimide dyads, Pz[60]–NI derivatives present stronger fluorescence intensity. Electrochemical study revealed that Pz[60]–NI presents better electron accepting character than the parent C60. The natural bond orbital of the dyads were calculated using density functional theory method and found that the sp3 nitrogen atom in the pyrazoline ring plays a key role in the charge transfer process.

A conformationally restricted uniconazole analogue as a specific inhibitor of rice ent-kaurene oxidase, CYP701A6

The plant growth retardant uniconazole (UNI), which has been used as an effective inhibitor of ent-kaurene oxidase (CYP701A) involved in gibberellin biosynthesis, also strongly inhibits ABA 8′-hydroxylase (CYP707A), a key enzyme in abscisic acid catabolism. Azole P450 inhibitors bind to the P450 active site by both coordinating to the heme-iron atom via an sp2 nitrogen and interacting with surrounding protein residues through a lipophilic region. We hypothesized that poor selectivity of UNI may result from its small molecular size and flexible conformation that allows it to fit into active sites differing in size and shape. To find a selective inhibitor of CYP701A based on this hypothesis, we examined inhibitory activities of three types of UNI analogues, which were conformationally constrained, enlarged in width, and enlarged in length, against recombinant rice CYP701A6 and Arabidopsis CYP707A3. Conformationally restricted analogues, UFAP2 and UFAP2N, inhibited CYP701A6 as strongly as UNI, whereas it inhibited CYP707A3 less than UNI.

Critical role of weak [C–H⋯O] hydrogen bonds in the assembly of benzo[1,2-d:4,5-d′]bisoxazole cruciforms into supramolecular sheets

This paper explores the structural patterns adopted by a class of eight conjugated cruciforms based on a benzo[1,2-d:4,5-d′]bisoxazole (BBO) nucleus. Within the series, the lengths of cruciforms' x- and y-axes, as well as their terminal substituents, were varied. Two new cruciforms have been prepared using microwave-assisted Sonogashira couplings. Examination of molecular structures of BBO cruciforms revealed the expected cross-shaped geometries, with ∼90° crossing angles between the two conjugation circuits. Most significant deviations from the idealized planar structures were caused by the distortion of benzene rings positioned along the cruciforms' y-axis from the plane of the central benzobisoxazole ring, by as much as 82.1°. Deviations from linearity within carbon–carbon triple bonds were mild, but additively resulted in notably bent y-axes of the two largest examined cruciforms. Most significantly, the packing patterns of benzobisoxazole cruciforms revealed three distinct organizational motifs. Cruciforms with carbonyl groups on either the horizontal or the vertical axis (or both) all organized into two-dimensional infinite sheets, apparently connected chiefly through [C–H⋯O] contacts that varied in length between 2.24 and 2.60 A, and could be interpreted as weak hydrogen bonds. The parallel layers of these two-dimensional sheets then assembled into three-dimensional structures through [π⋯π] stacking between the layers. The packing patterns of the two cruciforms with 4-(N,N-dimethylamino)phenyl groups on the vertical axis are dominated by one-dimensional columnar or tape-like assemblies that are formed through [π⋯π] stacking; these then organize into two-dimensional sheets, which in turn layer into a three-dimensional structure, but with a ∼60° angle between the adjacent sheets. Finally, in the parent tetraphenyl-substituted cruciform, the sp2 nitrogen on the BBO core plays the key role in the assembly. It establishes 2.64 A-long [C–H⋯N] contacts with the phenyl groups, mediating the formation of a unique packing pattern in which six tilted columnar assemblies of [π⋯π] stacked cruciforms surround a three-fold rotation axis in the crystal.

Changing the Palladium Coordination to Phosphinoimidazolines with a Remote Triazole Substituent

AbstractPhosphinoimidazoline (PHIM) ligands bearing a triazolylmethyl substituent at the sp3 nitrogen atom in the imidazoline ring lead to highly improved enantioselectivity (up to 99% ee) in allylic substitution reactions with respect to analogous ligands with substituents lacking the triazole unit. NMR and theoretical studies support a shift in the coordination mode of the PHIM ligand to palladium, triggered by a very favourable interaction with the triazole unit.

Rhodium(III)-Catalyzed Heteroannulation Route to Isoquinolines

Reported is the rhodium(III)-catalyzed synthesis of isoquinolines 3 from the reaction of O-acetyloximes 1 with alkynes 2 using a [Cp*RhCl2]2/NaOAc catalytic system. The reaction proceeds in good yields with diphenylacetylene using a wide range of R² = EDGs and EWGs. In case of meta R² substituents, a mixture of regio­isomeric isoquinoline 3 products was obtained. Unsymmetrical and dialkyl-substituted alkynes also afforded the isoquinolines, albeit in modest yields. Based on deuteriation studies, a mechanism involving ortho C-H activation of O-acetyl­oximes 1 via the oxime sp² nitrogen was proposed. Regioselective insertion of the alkyne into the arylrhodium intermediate leads to the formation of a seven-membered rhodacycle, which finally undergoes C-N reductive elimination. Analogously, isoxazol-5-ones 4 also undergo direct ortho-rhodation affording isoquinolines 5 with different R7 groups.

Ratiometric fluorescent determination of Zn(II): a new class of tripodal receptor using mixed imine and amide linkages

We synthesized a novel receptor with a unique combination of sp2 nitrogen (–CHN–) and carbonyl groups from amide linkages. These two moieties are judiciously incorporated into the receptor design such that these sites simultaneous binding a metal ion may generate a stable five-member ring. The receptor has been used to selectively detect Zn2+ through changes in the fluorescence spectra. Upon Zn2+ binding with the receptor, the fluorescence band shifted to enhance fluorescence intensity, allowing ratiometric determination of Zn2+ concentration.

Synthesis of Heterocycles by Intramolecular Nucleophilic Substitution at an Electron‐Deficient sp2 Nitrogen Atom

Abstract2‐Aryl(arylsulfonyl)‐6,7‐dihydro‐2H‐imidazo[2,1‐c][1,2,4]triazol‐3(5H)‐ones and 3‐arylimino‐6,7‐dihydroimidazo[2,1‐c][1,2,4]thiadiazoles have been synthesized by intramolecular nucleophilic substitution reactions at the electron‐deficient sp2 nitrogen atom of 2‐(hydroxyimino)imidazolidine O‐sulfonate. The displacement of the sulfate leaving group by both nitrogen and sulfur anionic nucleophiles proceeds exothermically by in‐plane SN2σ nucleophilic substitution.

Hydrogen‐Bond Accepting Strength of Five‐Membered N‐Heterocycles:The Case of Substituted Phenylpyrrolines and Myosmines

AbstractThe hydrogen‐bond (HB)accepting strengths of a series of five‐membered N‐heterocycles have been measured in CCl4 solution and/or calculated by theoretical methods. These molecules present a great chemical versatility, ranging from very weak π bases up to strongly HB acceptors, imines and amines. Among these compounds, special attention has been paid to myosmines, which are bifunctional molecules containing two very similar pyridinic and pyrrolinic sp2 nitrogen atoms. Infrared measurements provided the global HB basicities of these molecules, but the individual accepting strength of each nitrogen atom could not be achieved experimentally and had to be determined by theoretical calculations. Owing to their flexibility, the geometries of their different isomers were optimized and their basicities weighted by the calculated relative populations. To accurately estimate the individual HB strength of a nitrogen site, it was necessary to take into account a specific halogen bond between the second nitrogen atom and a solvent molecule. 1‐Pyrroline is a significantly stronger base than pyridine, but irrespective of the substituent on the pyridine ring, the pyrrolinic site is always the weakest HB acceptor in the myosmine molecules.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Application of Chiral Amine-Imine Ligands in Palladium-Catalyzed Polyketone Synthesis: Effect of Ligand Backbone on the Polymer Stereochemistry

Two pairs of enantiomerically pure chiral bidentate nitrogen-donor ligands (N*-N) featuring one sp3 and one sp2 nitrogen atom have been applied to the CO/vinyl arene copolymerization reaction catalyzed by the corresponding monocationic palladium(II) complexes [Pd(CH3)(CH3CN)(N*-N)][PF6]. The ligand fragment containing the sp2 nitrogen atom is a 2-pyridinyl or an 8-quinolinyl building block, while the chiral framework of the ligand derives from (S)-(+)-2,2′-(2-azapropane-1,3-diyl)-1,1′-binaphthalene or from trans-2,5-dimethylpyrrolidinyl. Ligands with the binaphthyl moiety generate catalysts showing a moderate activity, while ligands having the pyrrolidinyl fragment result in very low activity species. The stereochemistry of the synthesized polyketones depends on the sp2 nitrogen-containing fragment: ligands with the 2-pyridinyl group lead to atactic copolymers, whereas those with the quinolinyl moiety give an isotactic polyketone. The effect of the nature of the quinone, added to the reaction mixture as oxidant, has been investigated. MALDI-TOF analysis reveals the formation of several polymeric chains, differing in the presence of various end-groups.

Synthesis of calix[4]arene-based dipodal receptors: Competitive solvent extraction and liquid bulk membrane transport for selective recovery of Cu2+

A series of new p-tert-butylcalix[4]arene-based dipodal receptors are synthesised in high yields. The calix[4]arene units of all the receptors have been found to be present in cone conformation. To optimise the good extraction ability and high transport rate, we synthesised the receptors that differ from each other in their end groups. These receptors extract Cu2+ ion selectively from the buffered aqueous medium containing a mixture of metal ions. The receptor bearing four sp3 nitrogens has by far the greater ability to extract Cu2+ than the other receptors. All these receptors were effectively used for Cu2+ ion transport from the aqueous buffered source phase to the aqueous receiving phase.

Design, synthesis, and biological activity of piperidine diamine derivatives as factor Xa inhibitor

Previously, we identified cyclohexane diamine derivative 1 as orally bioavailable factor Xa inhibitor. We have investigated two racemic cis-piperidine diamine derivatives 2 and 3 based on 1. Compounds 2a– e showed higher fXa inhibitory activity, anticoagulant activity, and aqueous solubility than 3a– e having same substituent. Compounds 2a, 2c, 2e, and 2g– m having sp2 nitrogen, especially amide and urea derivatives, showed potent anticoagulant activity. Compounds 2h and 2k showed high oral activities in rats.