Nitrogen Lone Pair Research Articles

Synthesis of seven-membered fused sultones by reductive Heck cyclization: an investigation for stereochemistry through DFT study

An efficient method for the synthesis of seven-membered fused sultones via Pd(0) catalyzed intramolecular reductive Heck cyclization is reported. The method offers the regio- and stereoselective synthesis of highly functionalized benzopyrido-fused or dibenzo-fused sultone derivatives in 80–95% yield under mild conditions. Chemoselective Sonogashira coupling is utilized for the synthesis of cyclization precursors. The stereochemistry of the exocyclic double bond of sultone derivatives is confirmed from single crystal X-ray diffraction. The stereochemistry of the exocyclic double bond in dibenzo-fused sultones is reverse with reference to that of benzopyrido-fused sultones due to the presence of an interaction between the lone pair of nitrogen in pyridine with the electron deficient Pd(II). This interaction is confirmed through DFT (density functional theory) studies. The mechanistic role of water is established through deuterium exchange reaction.

Solvent effect on the fluorescence response of hydroxycoumarin bearing a dipicolylamine binding site to metal ions.

The fluorescence behavior of a probe dpa-HC, which has a coumarin derivative that acts as a fluorophore and a dipicolylamine (DPA) unit that functions as a metal ion-recognition site, was investigated with various metal ions in aqueous and several non-aqueous solvents. In aqueous solution, the fluorescence of dpa-HC was enhanced by Zn(2+) and Cd(2+), but was quenched by other metal ions. On the other hand, in an acetonitrile solution, only Mg(2+) enhanced the fluorescence, and the addition of a small amount of water quenched this fluorescence. This dramatic selectivity change is explained by stabilization of a metal-dpa-HC complex due to acetonitrile coordination and ON-OFF switching of the intramolecular photoinduced electron transfer (PET) from the nitrogen lone pair of DPA to the coumarin derivative.

Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

The synthesis of a series of imidazole styrylindoles and sulfonyl styrylindoles derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylindoles as potent inhibitors with activity greater or comparable with the standard ketoconazole.Flexible alignment and docking studies of the inhibitors in the CYP24A1 enzyme active site confirmed that complete occupation of the vitamin D access tunnel is essential to inhibitory activity, allowing exposure to multiple hydrophobic binding interactions and optimal conformation for the interaction of the imidazole nitrogen lone pair and the active site haem.

A novel electrochemical and chromogenic guest-responsive anisidine-based chemosensor for transition metallic cations

A new family of N,N-disubstituted p-anisidine-based electroactive ligands bearing dipyridinylamino- (1), difuranylamino- (2) and dithiophenylamino- (3) binding sites has been prepared by reductive alkylation of anisidine. The electrochemical investigations, in 0.1mol/dm−3 LiClO4 acetonitrile solution, showed that upon the addition of metallic cations, the redox features of 1 underwent drastic changes due to the cation chelation. The chemosensor complexation with Ni(II), Zn(II), Cd(II) and Pb(II) led to large anodic shifts of the oxidation potential peaks up to 700mV depending on the metal cation. A particularly high sensitivity toward nickel(II) with a higher selectivity to zinc(II) were observed. However, in the same conditions, thiophenyl- and furfuranyl- derivatives showed no sensitivity for any of the investigated cations. Moreover, UV–visible spectroscopy studies of 1 showed that the compound can act as a chromogenic guest-responsive and in presence of metallic cations, the absorption bands of compound 1 shifted due to a participation of the nitrogen lone pairs in the cation complexation. UV–visible spectroscopy did also allow to distinguish between the Ni(II) and Zn(II) complexes. Electrochemical and UV–visible spectroscopic investigations showed that the complexes have 1:2 stoichiometry [M(1)2]2+ (M: Zn, Ni, Cd and Pb).

Interaction of tryptophan and related compounds with oxygen- and carbon-centered radicals

Effects of tryptophan, 5-hydroxytryptophan, serotonin, and melatonin on final product formation during radiolysis of deaerated and oxygen-saturated ethanol and aqueous 1M ethanol solutions were studied. The named amino acids were found to be capable of adding α-hydroxyethyl radicals, thereby suppressing recombination reactions of these species. Unlike melatonin, tryptophan, 5-hydroxytryptophan, and serotonin were able to reduce oxygen-centered radicals being formed on radiation-chemical oxidation of ethanol in the presence of oxygen via electron transfer from the amine nitrogen lone pair.

Iridium-catalyzed C-H borylation of pyridines.

The iridium-catalysed C-H borylation is a valuable and attractive method for the preparation of aryl and heteroaryl boronates. However, application of this methodology for the preparation of pyridyl and related azinyl boronates can be challenged by low reactivity and propensity for rapid protodeborylation, particularly for a boronate ester ortho to the azinyl nitrogen. Competition experiments have revealed that the low reactivity is due to inhibition of the active catalyst through coordination of the azinyl nitrogen lone pair at the vacant site on the iridium. This effect can be overcome through the incorporation of a substituent at C-2. Moreover, when this is sufficiently electron-withdrawing protodeborylation is sufficiently slowed to permit isolation and purification of the C-6 boronate ester. Following functionalization, reduction of the directing C-2 substituent provides the product arising from formal ortho borylation of an unhindered pyridine ring.

Channeling the SmI₂ reactions to the radical path: radicals resisting reduction by SmI₂.

Studies on the reaction of 4-(2,2-diphenylvinyl)pyridine with SmI2 revealed that the intermediate radical strongly resists further reduction to the corresponding anion. The resistance of the radical to accepting another electron is traced to its stabilization by the nitrogen lone pair. The literature suggests that oxygen may also play a role similar to that of nitrogen in directing the course of the reaction toward radical rather than to anionic chemistry.

HERON reactions of anomeric amides: understanding the driving force

Calculations show that anomeric amides, amides bearing two electronegative atoms at the amide nitrogen, are unusual in structure and reactivity. They have much reduced amide resonance and also undergo the HERON reaction where anomeric destabilisation results in migration of one substituent from nitrogen to the carbonyl and formation of a resonance‐stabilised nitrene. B3LYP/6‐31G(d) calculations demonstrate how resonance and HERON reactivity are affected by bisalkoxyl substitution and aminoalkoxyl substitution at nitrogen. Because transition state structures for model reactions of N,N‐dimethoxyacetamide and N‐methoxy‐N‐dimethylaminoacetamide demonstrate complete loss of amide resonance, the overall barriers to their HERON reactions can be partitioned into a resonance (RE) and a rearrangement component (Erearr). REs for both amides have been calculated by isodesmic methods (carbonyl substitution nitrogen atom replacement and a calibrated trans amidation method), and the reduction in total electronegativity at the amide nitrogen in N‐methoxy‐N‐dimethylaminoacetamide results in an increase in amide resonance of about 4 kcal mol−1 relative to N,N‐dimethoxyacetamide (RE of 8.6 kcal mol−1). However, there is a large decrease in Erearr by some 20 kcal mol−1 to 10 kcal mol−1. Changes in these energies are rationalised on the basis of an increase in amide nitrogen lone pair energy, which increases resonance, and a higher energy substituent nitrogen lone pair enhancing the nN―σ*NO anomeric effect and the ease of rearrangement. Intramolecular HERON reactions in twisted 1‐aza‐2‐adamantanones, with no amide resonance, support the above variations in the rearrangement components to the activation barriers. On the strength of these findings, hydroxamic esters with only one oxygen at nitrogen will not undergo HERON reactions. Copyright © 2014 John Wiley & Sons, Ltd.

Synthesis, spectroscopic and conformational analysis of 1,4-dihydroisonicotinic acid derivatives

Structural and conformational properties of 1,4-dihydroisonicotinic acid derivatives, characterized by ester, ketone or cyano functions at positions 3 and 5 in solid and liquid states have been investigated by X-ray analysis and nuclear magnetic resonance and supported by quantum chemical calculations. The dihydropyridine ring in each of the compounds exists in flattened boat-type conformation. The observed ring distortions around the C(4) and N(1) atoms are interrelated. The substituent at N(1) has great influence on nitrogen atom pyramidality. The 1H, 13C and 15N NMR chemical shifts and coupling constants are discussed in terms of their relationship to structural features such as character and position of the substituent in heterocycle, N-alkyl substitution and nitrogen lone pair delocalization within the conjugated system.

Substituent effects on rates and torquoselectivities of electrocyclic ring-openings of N-substituted 2-azetines.

Transition structures for the conrotatory electrocyclic ring-opening reactions of N-substituted 2-azetines were computed with the density functional M06-2X/6-31+G(d,p). A wide range of substituents from π acceptors (e.g., CHO, CN) to π donors (NMe2, OMe) was explored. Acceptor substituents delocalize the nitrogen lone pair and stabilize the reactant state of 2-azetines, while donors destabilize the 2-azetine reactant state. The conrotatory ring-opening is torquoselective, and the transition state for the outward rotation of the N-substituent and inward rotation of the nitrogen lone pair is preferred. This transition structure is stabilized by an interaction between the nitrogen lone pair and the vacant π* orbital. The activation free energies are linearly related to the reaction free energies and the Taft σR(0) parameter.

NMR analysis and tacticity determination of poly(lactic acid) in C5D5N

Poly(lactic acid), (PLA), is a well known bioplastic derived from agri-based renewable materials. Because PLA's material properties depend largely on its tacticity, an improved test method for PLA tacticity would be useful. NMR analysis of PLA tacticity is revisited in this work, especially the assignments of NMR peaks from CH carbon and CH3 proton at the tetrad level in deuterated pyridine. The methyl protons are better resolved in pyridine due to solvent effects such as ring current shielding of the aromatic ring and electric field effect from the nitrogen lone pair. As an aid for the tacticity assignments, two-dimensional NMR spectra of poly(DL-lactic acid) (L/D = 50/50) and relative intensities of PLA samples have been used. The new assignments provide more detailed understanding of the 1H and 13C NMR spectra of PLA.

Spectral analysis, structural elucidation and evaluation of chemical reactivity of synthesized ethyl-4-[(2-cyano-acetyl)-hydrazonomethyl]-3,5-dimethyl-1H-pyrrole-2-carboxylate through experimental studies and quantum chemical calculations

This paper describes the synthesis, spectral analysis, structural elucidation and chemical reactivity of pyrrole hydrazide–hydrazone: ethyl-4-[(2-cyano-acetyl)-hydrazonomethyl]-3,5-dimethyl-1H-pyrrole-2-carboxylate (ECAHDPC). The 1H, 13C NMR isotropic chemical shifts and electronic absorption spectra have been calculated by GIAO and TD-DFT methods, respectively, and corroborate well with experimental data. The NH proton of the hydrazide–hydrazones (CNNHCO) frame appears as singlet at δ=11.69ppm due to delocalization of nitrogen lone pair with carbonyl group and its proton involvement in intramolecular H-bonding. The calculated wavenumbers of dimer are in good agreement with the experimental results and confirm that the stable conformer forms dimer by hydrogen bonding interactions between pyrrolic NH and carbonyl CO group of ester giving red shift and resonance assisted hydrogen bonding. The binding energy of intermolecular interaction is found to be 10.19kcal/mol after basis set superposition error correction. QTAIM calculations confirm the existence of intermolecular conventional hydrogen bond (NH⋯O), intra and intermolecular non-conventional hydrogen bond (CH⋯O) and intramolecular interaction (C⋯N). The NBO analysis has been performed to evaluate charge transfer and delocalization of electron density. The static first hyperpolarizability (β0) of monomer has been found to be 6.59×10–30esu. The maximum value of reactivity descriptors (fk+, sk+, ωk+) at C(9) indicate that this site is more susceptible to nucleophilic attack, favoring for the formation of heterocyclic compounds.

Anomeric effects in fluoro and trifluoromethyl piperidines: a computational study of conformational preferences and hydration

A computational investigation of anomeric effects in piperidine rings bearing fluoro and trifluoromethyl substituents shows for both compounds the most pronounced evidence of the anomeric effect, as expressed as hyperconjugative delocalization of the nitrogen lone pair, in structures with the substituent in the axial position and the N–H bond in the equatorial position. This structure is the lowest-energy structure in the fluoro case but not in the trifluoromethyl case where there is an increased axial penalty associated with the CF3 group. The anomeric effect is characterized via geometrical evidence, natural bond orbital analysis, electrostatic effects, and energetic criteria. Computational results from a variety of levels of theory are presented including CCSD(T) with complete basis set extrapolation, B2PLYP-D, ωB97XD, B97-D, M06-2X, B3LYP, and MP2 allowing for a comparison of performance. The CCSD(T)/CBS results are very well represented by either B2PLYP-D or ωB97XD with moderate to large basis sets (aug-cc-pVTZ or aug-cc-pVDZ). Hyperconjugation, electrostatic effects, and steric effects play a role in the relative energetic ordering of the isomers considered.

Switching Off the Charge Transfer and Closing the S1–T1 ISC Channel in Excited States of Quinolizinium Derivatives: A Theoretical Study

Excited states of benzo[b]quinolizinium (BQ) derivatives that show efficient pH-responsive fluorescence switching properties were studied quantum-chemically by employing the CASSCF/CASPT2 and TD-DFT methods. Protonation of aminophenyl-BQ at the electron-donor amine moiety converts the nitrogen lone pair into a σ bond and the HOMO into a lower-lying orbital that is no longer involved in the excitation, thereby rationalizing the suppression of the charge transfer. An S1-T1 seam between the vertically excited Franck-Condon (FC) point and the S1 equilibrium geometry favors intersystem crossing (ISC). The T1 state of the protonated form remains well below S1 (1.5 eV) because of favorable exchange interactions, whereas the T1 state of the unprotonated form does not experience any analogous stabilization because of the difference in the spatial domains of the singly occupied orbitals in the S1 and T1 states. The S1 surface from the FC point until the equilibrium geometry for the protonated species is energetically downhill. Calculations on models and available experimental data suggest design principles for similarly functioning pH-responsive species, namely, an amine lone pair as the electron donor and a cationic ring of moderate size as the electron acceptor that are structurally separated by virtue of a spacer.

Chemical Implications of Incompatible Ligand versus Metal Coordination Geometry Preferences

Binding an electron deficient pincer ligand which strongly dictates planar, mer stereochemistry, to a metal which prefers tetrahedral structure, e.g., d(10) CuCl, is explored for possible intramolecular redox chemistry. Experiment shows that the pincer ligand 2,2'-bis-tetrazinyl pyridine, btzp, forms a complex (btzp)CuCl which is a chloride-bridged polymer in the solid state, hence with 20 valence electrons around copper. DFT calculations show that even the monomer has nonplanar copper with the tetrazinyl nitrogen lone pairs somewhat misdirected away from copper, with long Cu/N bonds, in a singlet ground state; 13.9 kcal/mol less stable is a triplet, whose electronic structure shows one electron from the ground state Cu(I) has been transferred to a pincer π* orbital. Outer sphere electron transfer to (btzp)CuCl yields (btzp)Cu where the added electron has gone into the pincer, to leave a ligand-centered radical, characterized by EPR, chemical reactivity, and X-ray photoelectron spectroscopy.

Theoretical 14N and 17O nuclear quadrupole resonance parameters for tirapazamine and related metabolites

Density functional theory (DFT) calculations were performed to realize the effects of the N–O group on the reactivity and electronic properties of 3-amino-1,2,4-benzotriazines. The electric field gradient, EFG, tensors of 14N and 17O nuclei and natural bond orbital (NBO) analysis in the tirapazamine (TPZ) and its four derivatives were calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) method in the gas phase. The NBO analysis reveal that the bond strength, proton affinity and position of N–O group in the heterocyclic ring have major influence on the reactivity of considered molecules. Accordingly, we suggest that the TPZ and 4-oxide (d) structures due to having a weaker N–O bond with larger negative charge on the oxygen atom at the 4-position are more active than the other ones. Calculated 14N and 17O EFG tensors were used to evaluate nuclear quadrupole coupling tensors, χ, and asymmetry parameters, η Q . Results showed that oxidation of a nitrogen atom at any position have significant influence on its 14N nuclear quadrupole resonance (NQR) parameters. Also, the occupancy of nitrogen lone pair plays an important role in determination of the q zz and χ values of mentioned nuclei. It is found that the η Q and χ are appropriate parameters to study the contribution of lone pair electrons of nitrogen atom in the formation of chemical bond or conjugation with the aromatic system. Finally, a linear correlation is observed between the χ(14N) and χ(17O) values in the N–O bond which may be associated with the reactivity of these compounds.

Polaronic Relaxation by Three-Electron Bond Formation in Graphitic Carbon Nitrides

We apply density functional and ionization potential equation of motion coupled cluster theories to investigate hole transport in graphitic carbon nitride (g-C3N4), an organic photocatalyst which drives water splitting and oxidative organic reactions. Calculations on small cationic model clusters suggest that the formation of two-center, three-electron bonds involving lone pair electrons on the nitrogen atoms of adjacent monomer units in g-C3N4 results in the localization of positive charge; reorganization energies for polaron hopping range from 1.3 to 2.1 eV depending on whether the material is fully condensed into a two-dimensional sheet or linearly polymerized. Similarly, the chemical character of the valence band maximum (VBM) is determined by the strength of the antibonding interaction between lone pair electrons on neighboring monomers; the fully condensed material has a VBM composed predominantly of nitrogen lone pair electrons, whereas the polymer exhibits a VBM of π character.

Chemical post-treatment and thermoelectric properties of poly(3,4-ethylenedioxylthiophene):poly(styrenesulfonate) thin films

We report on the modification of the thermoelectric properties of poly(3,4-ethylenedioxylthiophene):poly(styrenesulfonate) (PEDOT:PSS) thin films by means of a simple post treatment of the solid thin films realized by drop-coating. We show that the organic polar solvents, dimethyl sulfoxide and ethylene glycol as secondary dopants for PEDOT:PSS, only affect the film morphology for which a high electrical conductivity is observed. In contrast, ethanolamine (MEA) and ammonia solutions are reduction agents that improve the density of PEDOT chains in the reduced forms (polaron and neutral states), resulting in the trade-off between Seebeck coefficient and electrical conductivity. Furthermore, we show that the nature of amines determines the reduction degree: the nitrogen lone pair electrons in MEA are easier to be donated than those in ammonia solution and will therefore neutralize the PEDOT chains.

O-vs. N-protonation of 1-dimethylaminonaphthalene-8-ketones: formation of aperiN–C bond or a hydrogen bond to the pi-electron density of a carbonyl group

Peri-amino-naphthylketones protonate onOorNforming a longperi-N–C bond or a hydrogen bond to the ketone's π-density.

Unfolding the crucial role of a nucleophile in Ziegler-Natta type Ir catalyzed polyaminoborane formation.

formation through dehydropolymerization of ammonia-borane by Brookhart's iridium pincer catalyst has been under intense scrutiny but a sound molecular level understanding has remained elusive. Herein, using DFT the mechanism outlined by us for IrH2POCOP catalyzed formation underscores the importance of generation of nucleophiles, in particular that of the metal bound NH2BH2 moiety armed with a nitrogen lone pair for chain initiation and chain propagation steps.