Terminal Nitrogen Atom Research Articles

Tricyanomethane or Dicyanoketenimine-Silylation makes the Difference.

Pseudohalides such as tricyanomethanide, [C(CN)3]-, are well known in chemistry, biochemistry and industrial chemistry. The protonated species HC(CN)3, a classic hydrogen pseudohalide Brønsted acid, is a very strong acid with a pKa value of -5. However, HC(CN)3 is difficult to handle as it tends to decompose rapidly or, more precisely, to oligo- and polymerize. Therefore, silylated pseudohalide compounds with the [Me3Si]+ as the "big organometallic proton" have become interesting, exhibiting similar chemical properties but better kinetic protection. Here, the stepwise silylation of the pseudohalide anion [C(CN)3]- is reported, forming the heavier homologue of HC(CN)3, namely [Me3Si][C(CN)3], and in presence of two additional [Me3Si]+ cations even the dicationic species [(Me3Si-NC)3C]2+ as stable [B(C6F5)4]- salt. Surprisingly, in contrast to the protonated species HC(CN)3, in which the proton is bound to the central carbon atom of [C(CN)3]-, silylation of the [C(CN)3]- anion occurs at one of the three terminal nitrogen atoms, thus forming the long-sought dicyanoketenimine [Me3Si-NC-C(CN)2]. All further silylation steps take place exclusively on the terminal N atoms of the three CN groups and not on the central carbon atom, until the intriguing, highly symmetrical dication, [(Me3Si-NC)3C]2+, is finally generated. The experimental data are supported by quantum chemical calculations in terms of thermodynamics and chemical bonding.

Isotopomer labeling and oxygen dependence of hybrid nitrous oxide production

Abstract. Nitrous oxide (N2O) is a potent greenhouse gas and ozone depletion agent, with a significant natural source from marine oxygen-deficient zones (ODZs). Open questions remain, however, about the microbial processes responsible for this N2O production, especially hybrid N2O production when ammonia-oxidizing archaea are present. Using 15N-labeled tracer incubations, we measured the rates of N2O production from ammonium (NH4+), nitrite (NO2-), and nitrate (NO3-) in the eastern tropical North Pacific ODZ and the isotopic labeling of the central (α) and terminal (β) nitrogen (N) atoms of the N2O molecule. We observed production of both doubly and singly labeled N2O from each tracer, with the highest rates of labeled N2O production at the same depths as the near-surface N2O concentration maximum. At most stations and depths, the production of 45N2Oα and 45N2Oβ were statistically indistinguishable, but at a few depths there were significant differences in the labeling of the two nitrogen atoms in the N2O molecule. Implementing the rates of labeled N2O production in a time-dependent numerical model, we found that N2O production from NO3- dominated at most stations and depths, with rates as high as 1600 ± 200 pM N2O d−1. Hybrid N2O production, one of the mechanisms by which ammonia-oxidizing archaea produce N2O, had rates as high as 230 ± 80 pM N2O d−1 that peaked in both the near-surface and deep N2O concentration maxima. Based on the equal production of 45N2Oα and 45N2Oβ in the majority of our experiments, we infer that hybrid N2O production likely has a consistent site preference, despite drawing from two distinct substrate pools. We also found that the rates and yields of hybrid N2O production were enhanced at low dissolved oxygen concentrations ([O2]), with hybrid N2O yields as high as 20 % at depths where [O2] was below detection (880 nM) but nitrification was still active. Finally, we identified a few incubations with [O2] up to 20 µM where N2O production from NO3- was still active. A relatively high O2 tolerance for N2O production via denitrification has implications for the feedbacks between marine deoxygenation and greenhouse gas cycling.

Structural Elucidation of N2O Clusters at Low Temperatures: Exemplary Framework Stabilized by π-Hole-Driven N···O and N···N Pnicogen Bonding Interactions.

N2O is a classic prototype, in which central nitrogen is sufficiently electropositive with a positive potential of 20 kcal mol-1 in magnitude to qualify it as a possible pnicogen. This was applied to a test with N2O clusters using ab initio calculations in association with various molecular topographic tools. The structure of the energetically dominant and N2O dimer was in favor of a perpendicular geometry, where the central nitrogen atom of the N2O submolecule assumed a near 90° angle with the adjacent N═O and/or N═N moiety, which provides the affirmation of central nitrogen as a possible π-hole-driven pnicogen. The terminal nitrogen and oxygen atoms of N2O continue to act as conventional electron donors (Lewis bases) with a negative potential. Overall, predominant π-hole-driven N···O and N···N pnicogen bonding interactions were observed to stabilize N2O clusters. Furthermore, N2O clusters (dimers and trimers) were synthesized at low temperatures in an Ar matrix using molecular beam (effusive and supersonic expansion) experiments. The geometries of these clusters were characterized by probing infrared spectroscopy with corroboration from ab initio computational methods. In addition to our previously investigated nitromethane and nitrobenzene systems, N2O also makes it to a pnicogen bonder's club with the central nitrogen as a π-hole-driven pnicogen.

Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson's Disease Therapeutics.

The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson's disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor's brain accessibility. Our strategy involved the synthesis of macrocyclic molecules by linking the two terminal nitrogen atoms of HG-10-102-01 with an alkyl chain ranging from 2 to 4 units, laying the groundwork for innovative LRRK2 inhibitor designs. Through meticulous computational and synthetic optimization of both biochemical efficacy and BBB permeability, 9 out of 14 synthesized candidates demonstrated potent low-nanomolar inhibition and significant BBB penetration. Further assessments of in vitro and in vivo effectiveness, coupled with pharmacological profiling, highlighted 8 as the promising new lead compound for PD therapeutics.

Mechanistic Insights Into the [3+1] Cycloadditions of Me3SiN3 on Bis‐Silylene and the Formation of Pseudo‐Silaazatriene

AbstractThe reaction mechanism for the formation of the pseudo‐silaazatriene 1 (LN(SiMe3)2−Si−N−Si(L)NSiMe3; L=PhC−(NtBu)2) by the reaction of 1 equivalent of bis‐silylene (LSi−SiL; L=PhC(NtBu)2) with 3 equivalents of azide Me3SiN3 has been explored at M06/def2‐TZVPP//BP86‐D3(BJ)/def2‐TZVPP level of theory. The reaction mechanism is guided by the high Lewis basicity of the silicon lone pair and the high Lewis acidic character of Si−N bonds, as well as by the high tendency to eliminate N2 from Me3SiN3. The first step of the reaction is the formation of [3+1] cycloaddition product (I1) by the synergetic interactions of the lone pair on the silylene silicon with the π* molecular orbital of Me3SiN3 which is majorly localized on the terminal nitrogen atom, and the donation of the σ‐type lone pair on the nitrogen atom connected to the SiMe3 group with the Si−N σ* orbital on silylene. The elimination of N2 from I1 results in the formation of pseudo‐silaimine intermediate I2 having a dicoordinated, monovalent nitrogen atom. The most favourable pathway involves the second addition of Me3SiN3 followed by N2 elimination resulting bis‐silaimine intermediate I4‐P2. The highly reactive lone pair on the dicoordinated, monovalent nitrogen atom can be coordinated to the Si−N σ* MO of the second silylene moiety resulting in Si−N bond formation and Si−Si bond cleavage. This step is similar to the SN2′ reaction where the incoming nucleophile and the leaving group are on the same side resulting in the formation of silaimine I5. Further, the [3+1] cycloaddition of one more molecule of Me3SiN3 followed by N2 elimination results in the formation of silaimine intermediate I7. I7 undergoes 1,3‐silyl migration leading to the final product 1. The lone pairs on di‐ and tricoordinated nitrogen centres of all the intermediates are stabilized by hyperconjugative interactions. The delocalized hyperconjugative interaction stabilizes the lone pairs in 1.

Reaction mechanism of acetonitrile, olefins, and amines catalyzed by Ag2CO3: A DFT investigation

AbstractThe mechanism of Ag2CO3‐catalyzed reactions of acetonitrile, olefins, and amines was investigated by using the M06‐L‐D3/6‐311 + G(d,p) method and level, and solvation model based on solute electron density (SMD) model was applied to simulate the solvent effect. Calculations show that the Ag2CO3 could achieve the Csp3‐H activation by coordinating with the terminal nitrogen atom of CH3CN; then, the addition reaction happened between the obtained Ag‐complex intermediate and olefin via the coordination of Ag and benzene ring; finally, the obtained radical intermediate continues to go through one single electron transfer (SET) process, addition reaction, and H‐shift reaction to yield the final product. The computational results reveal that Fe3+ cation would have assisted the SET process successfully and the path of direct addition with the amine is the optimal. Fukui function and dual descriptor can be used to predict the reactive sites, and electron spin density isosurface graphs can analyze the structures and reveal the substances.

Photocatalytic Boryl Radicals Triggered Sequential B─N/C─N Bond Formation to Assemble Boron-Handled Pyrazoles.

Vinyldiazo compounds are one of the most important synthons in the construction of a cyclic ring. Most photochemical transformations of vinyldiazo compounds are mainly focusing on utilization of their C═C bond site, while reactions taking place at terminal nitrogen atom are largely unexplored. Herein, a photocatalytic cascade radical cyclization of LBRs with vinyldiazo reagents through sequential B─N/C─N bond formation is described. The reaction starts with the addition of LBRs (Lewis base-boryl radicals) at diazo site, followed by intramolecular radical cyclization to access a wide range of important boron-handled pyrazoles in good to excellent yields. Control experiments, together with detailed mechanism studies well explain the observed reactivity. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research.

Boron Insertion into the N≡N Bond of a Tungsten Dinitrogen Complex.

The 1,3-addition of 1,2-diaryl-1,2-dibromodiboranes (B2Br2Ar2) to trans-[W(N2)2(dppe)2] (dppe = κ2-(Ph2PCH2)2), which is accompanied by a Br-Ar substituent exchange between the two boron atoms, is followed by a spontaneous rearrangement of the resulting tungsten diboranyldiazenido complex to a 2-aza-1,3-diboraallenylimido complex displaying a linear, cumulenic B=N=B moiety. This rearrangement involves the splitting of both the B-B and N=N bonds of the N2B2 ligand, formal insertion of a BAr boranediyl moiety into the N=N bond, and coordination of the remaining BArBr boryl moiety to the terminal nitrogen atom. Density functional theory calculations show that the reaction proceeds via a cyclic NB2 intermediate, followed by dissociation into a tungsten nitrido complex and a linear boryliminoborane, which recombine by adduct formation between the nitrido ligand and the electron-deficient iminoborane boron atom. The linear B=N=B moiety also undergoes facile 1,2-addition of Brønsted acids (HY = HOPh, HSPh, and H2NPh) with concomitant Y-Br substituent exchange at the terminal boron atom, yielding cationic (borylamino)borylimido tungsten complexes.

The role of formamidine acetate as a complexing agent in the chemical mechanical polishing process of Ta-based barrier layers for through-silicon vias wafers

The complex agent can form a soluble complex with tantalum to improve the removal rate of tantalum (Ta), but the removal rate of tantalum is less than 1000 Å/min when the traditional complex agents such as citric acid, acetic acid, phosphoric acid, ammonium salt and oxalic acid are added to the slurry, which cannot meet the requirements of through-silicon via (TSV) process. Due to the various bonding forms of amidine and the easy modification of the substituent group on the terminal nitrogen atom, the metal complexes of amidine have different stereo effects and electronic properties, and are called "universal ligands". Formamidine acetate (FA) is a new complexing agent with great potential, which is suitable for the removal of TSV tantalum materials. In order to improve the rate selection ratio of Ta and copper (Cu) in the chemical mechanical polishing (CMP) of TSV wafer barrier materials, the effect of FA as a complexing agent on the removal rate of Ta and Cu and the rate selection ratio was investigated under the conditions of working pressure of 3 psi, polishing head speed of 87 r/min, polishing disk speed of 93 r/min, and flow rate of 300 mL/min. The complexation mechanism of FA on Ta and Cu was investigated by electrochemistry, X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and density functional theory (DFT), and the surface quality before and after polishing was compared by using atomic force microscope (AFM). The results showed that with an FA concentration of 1.5 wt%, the removal rates of Ta and Cu were 1503 Å/min and 516 Å/min respectively, which verified the obvious effect of FA on improving the rate selection ratio of Ta and Cu. Surface roughness for both metals decreased from pre-polishing values of 0.793 nm to post-polishing values of 0.210 nm for Ta; from pre-polishing values of 4.32 nm to post-polishing values of 0.381 nm for Cu indicating significant improvement in surface quality after treatment with FA.

Development of selective class I protein arginine methyltransferase inhibitors through fragment-based drug design approach

Protein arginine methyltransferases (PRMTs) catalyze the methylation of the terminal nitrogen atoms of the guanidino group of arginine of protein substrates. The aberrant expression of these methyltransferases is linked to various diseases, making them promising therapeutic targets. Currently, PRMT inhibitors are at different stages of clinical development, which validated their significance as drug targets. Structural Genomics Consortium (SGC) has reported several small fragment inhibitors as Class I PRMT inhibitors, which can be the starting point for rational drug development. Herein, we report the successful application of a fragment-based approach toward the discovery of selective Class I PRMT inhibitors. Structure-based ligand optimization was performed by strategic incorporation of fragment hits on the drug-like quinazoline core and subsequent fragment growth in the desired orientation towards identified hydrophobic shelf. A clear SAR was established, and the lead compounds 55 and 56 displayed potent inhibition of Class I PRMTs with IC50 values of 92 nM and 37 nM against PRMT4. We report the systematic development of potent Class I PRMT inhibitors with good potency and about 100-fold selectivity when tested against a panel of 31 human DNA, RNA, and protein lysine and arginine methyltransferases. These improved small molecules will provide new options for the development of novel potent and selective PRMT4 inhibitors.

Synthesis, crystal structures, photophysical and antibacterial properties of Ag(I) and Zn(II) coordination polymers based on a flexible bisacylhydrazone ligand

A flexible bisacylhydrazone ligand (H4L) was designed and synthesized from the condensation reaction of dialdehyde 3,3′-thiobis(methyiene)-bis-(5-methyl-salicylaldehyde) (b) with isonicotinic hydrazide. In the DMSO/methanol solution, two coordination polymers (CPs), formulated as {[Ag(H4L)NO3]·DMSO·2H2O}n (CP 1) and {[Zn2(H2L2-)2]·3DMSO·3H2O}n (CP 2), were synthesized from H4L with Ag(I) or Zn(II) ions, respectively. These two CPs were characterized via elemental analysis, FT-IR spectra, and single crystal X-ray determination. The results show that CP 1 exists as a 1D looped-chain polymer, while CP 2 exists as a 2D sheet polymer. The coordination configurations of the two CPs were analyzed and compared in detail, which disclose the terminal pyridyl nitrogen atoms exhibit obviously stronger coordination ability compared to other sites. In addition, photophysical, electrochemical and antibacterial properties of H4L and the two CPs were investigated.

Quantum-chemical study of the structure of amidinyltetramethoxycarbonylcyclopentadiene and its Hg(II) and Tl(I) complexes

DFT CAM-B3LYP/6-311++G(d,p) and CAM-B3LYP/6-311++G(d,p)/SDD calculations showed that the polydentate amidinyltetramethoxycarbonylcyclopentadienyl ligand and its Hg(II) and Tl(I) complexes are the most stable in the form of ylide isomers, in which the hydrogen or metal atom is bonded to the terminal nitrogen atom of the amidinium fragment and in the case of metal complexes, it is additionally coordinated by the π -system of the cyclopentadiene ring. Alternative isomers in which hydrogen or metal atoms are bonded to carbon atoms of the cyclopentadiene ring or to carbonyl oxygen atoms of methoxycarbonyl substituents are energetically less stable at Δ E ZPE = 4.1-15.1 kcal/mol.

Mechanistic DFT Study of 1,3-Dipolar Cycloadditions of Azides with Guanidine

Density functional calculations SMD(chloroform)//B3LYP/6-311+G(2d,p) were employed in the computational study of 1,3-dipolar cycloadditions of azides with guanidine. The formation of two regioisomeric tetrazoles and their rearrangement to cyclic aziridines and open-chain guanidine products were modeled. The results suggest the feasibility of an uncatalyzed reaction under very drastic conditions since the thermodynamically preferred reaction path (a), which involves cycloaddition by binding the carbon atom from guanidine to the terminal azide nitrogen atom, and the guanidine imino nitrogen with the inner N atom from the azide, has an energy barrier higher than 50 kcal mol-1. The formation of the other regioisomeric tetrazole (imino nitrogen interacts with terminal N atom of azide) in direction (b) can be more favorable and proceed under milder conditions if alternative activation of the nitrogen molecule releases (e.g., photochemical activation), or deamination could be achieved because these processes have the highest barrier in the less favorable (b) branch of the mechanism. The introduction of substituents should favorably affect the cycloaddition reactivity of the azides, with the greatest effects expected for the benzyl and perfluorophenyl groups.

Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19.

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.

Regioselective Cycloaddition of Nitrile Imines to 5-Methylidene-3-phenyl-hydantoin: Synthesis and DFT Calculations.

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths.

4-(All-yloxy)benzohydrazide.

The non-H atoms of the title compound, C10H12N2O2, are approximately coplanar with the exception of those at the ends: the terminal allyl carbon atom and terminal hydrazide nitro-gen atom are displaced from the mean plane by 0.67 (2) and 0.20 (2) Å, respectively. In the crystal, the mol-ecules are linked by N-H⋯O and N-H⋯N hydrogen bonds, which give rise a two-dimensional network propagating in the (001) plane.

Catalytic Nitrous Oxide Reduction with H2 Mediated by Pincer Ir Complexes.

Reduction of nitrous oxide (N2O) with H2 to N2 and water is an attractive process for the decomposition of this greenhouse gas to environmentally benign species. Herein, a series of iridium complexes based on proton-responsive pincer ligands (1-4) are shown to catalyze the hydrogenation of N2O under mild conditions (2 bar H2/N2O (1:1), 30 °C). Among the tested catalysts, the Ir complex 4, based on a lutidine-derived CNP pincer ligand having nonequivalent phosphine and N-heterocyclic carbene (NHC) side donors, gave rise to the highest catalytic activity (turnover frequency (TOF) = 11.9 h-1 at 30 °C, and 16.4 h-1 at 55 °C). Insights into the reaction mechanism with 4 have been obtained through NMR spectroscopy. Thus, reaction of 4 with N2O in tetrahydrofuran-d8 (THF-d8) initially produces deprotonated (at the NHC arm) species 5NHC, which readily reacts with H2 to regenerate the trihydride complex 4. However, prolonged exposure of 4 to N2O for 6 h yields the dinitrogen Ir(I) complex 7P, having a deprotonated (at the P-arm) pincer ligand. Complex 7P is a poor catalytic precursor in the N2O hydrogenation, pointing out to the formation of 7P as a catalyst deactivation pathway. Moreover, when the reaction of 4 with N2O is carried out in wet THF-d8, formation of a new species, which has been assigned to the hydroxo species 8, is observed. Finally, taking into account the experimental results, density functional theory (DFT) calculations were performed to get information on the catalytic cycle steps. Calculations are in agreement with 4 as the TOF-determining intermediate (TDI) and the transfer of an apical hydrido ligand to the terminal nitrogen atom of N2O as the TOF-determining transition state (TDTS), with very similar reaction rates for the mechanisms involving either the NHC- or the P-CH2 pincer methylene linkers.

Synthesis and Extraction Properties of Diphenylphosphorylureas with ω-(Alkoxy/Tetrahydrofuryl)Alkyl Substituents at the Terminal Nitrogen Atom

Synthesis and Extraction Properties of Diphenylphosphorylureas with ω-(Alkoxy/Tetrahydrofuryl)Alkyl Substituents at the Terminal Nitrogen Atom

Halogen Bond Motifs in Cocrystals of N,N,O and N,O,O Acceptors Derived from Diketones and Containing a Morpholine or Piperazine Moiety.

In this study, we investigate the halogen bond acceptor potential of oxygen and nitrogen atoms of morpholine and piperazine fragments when they are peripherally located on N,O,O or N,N,O acceptor molecules. We synthesized four acceptor molecules derived from either acetylacetone or benzoylacetone and cocrystallized them with 1,4-diiodotetrafluorobenzene and 1,3,5-triiodotrifluorobenzene. This resulted in eight cocrystals featuring different topicities and geometric dispositions of donor atoms. In all cocrystals, halogen bonds are formed with either the morpholinyl oxygen atom or the terminal piperazine nitrogen atom. The I···Omorpholine halogen bonds feature lower relative shortening values than I···Nterminal, I···Ocarbonyl, and I···Nproximal halogen bonds. The N and O halogen bond acceptor sites were evaluated through calculations of molecular electrostatic potential values.

DFT study of the role of substituents in tin(II) bis(amidoethyl)amine complexes used for ε-caprolactone polymerization

DFT simulations of ring-opening polymerization of ε-caprolactone in the presence of two stannylenes based on bis(2-amidoethyl)amine ligands demonstrated that rate limiting step of the whole process is the nucleophilic attack of a metal initiator with the formation of the tetrahedral carbon from sp2 carbon atom of the carboxy group. The presence of electron-withdrawing groups at the terminal nitrogen atoms of the ligands leads to decrease in the activation energy of the rate limiting step.