Phenyl Azide Research Articles

Synthesis and Characterization of Some Heterocyclic Compounds and Evaluation of Antibacterial Activity

In this study, heterocyclic compounds with two nitrogen atoms are prepared by reaction of 2-aminobenzimidazole with formic acid to get amide derivatives (A), reacts with phenylhydrazine to get phenyl hydrazone derivatives (B), reacts with ethyl chloroacetate to obtain ethyl acetate derivatives (C). The derivative (D) obtains on heating in a basic medium. The (B) reacts with 2-chloroacetyl chloride to give derivatives (E). A number of Schiff bases are prepared (F, I) from reacting 2-aminobenzimidazole with benzaldehyde derivatives. The(F) reacts with propargyl bromide to give propargyl bromide derivatives (G). The cyclization with 4-nitrophenyl azide leads to obtain triazole compound (H). The compound (I) reacts with ethyl chloroacetate to give ethyl acetate derivatives (J), reacts with hydrazine to give N-amide hydrazine derivatives (K). The cyclization give rises to 1,3,4-oxadiazole derivatives (L). The compound (I) reacts with sodium azide to obtain tetrazole derivatives (M). Synthesizing of Triazine, Oxadiazole, Triazole, Tetrazole via cyclization of the Schiff base derivatives with ethyl chloroacetate and chloro acetyl chloride, benzoic acid, 4-nitrophenyl azide, sodium azide and phenyl azide are possible respectively. The FT-IR, 13C-NMR and 1H-NMR spectral data give good evidence for the formation of the compounds. Some prepared compounds exhibit antibacterial properties.

Methods for Acrolein Detection: Recent Advances and Applications

Acrolein holds excellent potential as a critical biomarker in various oxidative stress-related diseases, and direct measurement of acrolein in biological systems is becoming essential to provide information for diagnosis and therapeutic purposes. In this review, we will discuss some available techniques for the detection of acrolein from biological samples. A conventional analytical method for the detection of acrolein by using high-performance liquid chromatography analysis after derivatization with 3-aminophenol is available. However, it is not suitable for high-throughput assay and inconvenient for measurement in clinical practice. On the other hand, we have recently discovered that phenyl azide can rapidly and selectively react with acrolein in a click manner to provide 4-formyl-1,2,3-triazoline through 1,3-dipolar cycloaddition. Moreover, we have successfully utilized this acrolein-azide click reaction as a simple and robust method for detecting and visualizing acrolein generated by live cells. Herein, we will describe our reaction-based acrolein sensor and its application to detect and visualize breast cancer tissues. We utilized the azide-acrolein click reaction-based method to discriminate breast cancer lesion from the normal breast gland, which resected from breast cancer patients. This method is the first example of an organic synthetic chemistry-based approach that can be used not only to visualize the cancer tissue but also to distinguish morphology of the resected tissue only within a few minutes. It has a potential clinical application for breast-conserving surgery. Furthermore, the ability to perform chemical reactions with cancer metabolites only at the desired cancer site is highly advantageous for cancer therapy.

Photo-immobilization of pseudozwitterionic polymers with balanced electrical charge for developing anti-coagulation surfaces

This study aims to develop an economical coating agent that can easily impart excellent anti-coagulative property onto polymer surfaces. To this end, photo-reactable pseudozwitterionic polymer comprising cationic ammonium, anionic carboxylic acid, and photo-reactable phenyl azide group was synthesized via free-radical polymerization. Hydrophilicity, surface charge, surface elemental analysis, and anti-biofouling properties of the coated substrates were evaluated after photo-immobilizing the pseudozwitterionic polymer on the PET substrate. The pseudozwitterionic polymer was successfully immobilized; the coated substrate showed excellent anti-biofouling properties. Photo-immobilization of the pseudozwitterionic polymer was also confirmed to be effective in imparting anti-biofouling property onto the fibrous filtration membrane. The immobilized pseudozwitterionic polymer effectively prevented membrane blockage and safely filtered platelets from blood plasma.

Ortho-Cyclization in Asymmetrically Substituted Arylnitroso Oxides.

The mechanism of the photooxidation of a number of asymmetrically substituted phenyl azides in acetonitrile was studied. The key intermediates of this reaction are the corresponding nitroso oxides, the unimolecular consumption of which occurs via the cis form when the terminal oxygen atom of the NOO moiety reacts with the ortho position of the aromatic ring. As a result, it is opened to form a nitrile oxide. In the case of 3-methylphenyl azide, the reaction proceeds via the cis/syn form of nitroso oxide with a regioselectivity of 91%. The methoxy substituent at the para position changes the direction of the ortho-cyclization so that it occurs via the cis/anti form of nitroso oxide independently on the nature of a meta substituent. Nitrile oxides, which are formed as a result of these transformations of nitroso oxides, are stabilized by [3 + 2] cycloaddition with acetonitrile to give 1,2,4-oxadiazoles. The observed regioselectivity of the ortho-cyclization of nitroso oxides was explained using theoretical methods. Its cause consists in the extra-stabilization of the transition state of the reaction of the cis/anti form due to a stereoelectronic effect of the para-methoxy substituent.

Isomer-Selective Threshold Photoelectron Spectra of Phenylnitrene and Its Thermal Rearrangement Products.

The photoionization of phenylnitrene was investigated by photoion mass-selected threshold photoelectron spectroscopy in the gas phase. Flash vacuum pyrolysis of phenyl azide at 480 °C produces the nitrene, which subsequently rearranges at higher temperatures affording three isomeric cyanocyclopentadienes, in contrast to low-temperature trapping experiments. Temperature control of the reactor and threshold photoelectron spectra allows for optimizing the generation of phenylnitrene or its thermal rearrangement products, as well as obtaining vibrational information for the corresponding ions. The adiabatic ionization energies (AIE) of the triplet nitrene (3A2) to the radical cation in its lowest-energy doublet (2B2) and quartet (4A1) spin states were determined to 8.29 ± 0.01 and 9.73 ± 0.01 eV, respectively. Vibrational frequencies of ring breathing modes were measured at 500 ± 80 and 484 ± 80 cm-1 for both the [Formula: see text](2B2) and [Formula: see text](4A1) cationic states, respectively. The AIE differ from the values previously reported; hence, we revise the doublet-quartet energy splitting of the phenylnitrene radical cation to 1.44 eV, in excellent agreement with composite methods and coupled cluster calculations, but considerably higher than the literature reference (1.1 eV).

A molecular electron density theory study of the Grignard reagent‐mediated regioselective direct synthesis of 1,5‐disubstituted‐1,2,3‐triazoles

AbstractThe [3 + 2] cycloaddition (32CA) reaction of phenyl azide4with ethynylbenzene5in presence of ethyl magnesium bromide (EtMgBr) has been studied within the Molecular Electron Density Theory with the aim to rationalise the high‐yielding direct regioselective synthesis of 1,5‐disubstituted‐1,2,3‐triazoles. Topological analysis of the electron localisation function (ELF) of phenyl azide4indicates that it has azwitterionicstructure participating inzw‐type32CA reactions. Computed activation parameters along the two feasible reaction paths for this 32CA reaction makes the rationalisation of the experimental outcomes possible. Grignard reagent‐mediated processes have a polar character and complete regioselectivity, which is in line with the fast, clean, and high yielding reaction experimentally observed. The reaction follows aone‐stepmechanism involving a high asynchronous transition state structure. Topological analysis of the ELF and calculated quantum theory of atoms‐in‐molecule parameters indicate that formation of new C–N single bonds does not begin exactly at the corresponding transition state structure.

Unravelling the strain-promoted [3+2] cycloaddition reactions of phenyl azide with cycloalkynes from the molecular electron density theory perspective

The increase of the strain not only increases the reaction rate and the exothermic character of these reactions, but also changes the mechanism for the small cycloalkynes from a non-polar to a polar reaction.

Synthesis of Complex Boron-Nitrogen Heterocycles Comprising Borylated Triazenes and Tetrazenes Under Mild Conditions.

The reactions of organic azides with diaryl(dihalo)diboranes(4) were explored, resulting in the observation of a number of surprising reactivity patterns. The reaction of phenyl azide with 1,2-diaryl-1,2-dihalodiboranes(4) resulted in the formation of five-membered rings comprising diboryl-triazenes with retention of the boron-boron bond, while the reaction of the peculiar 1,1-di(9-anthryl)-2,2-difluorodiborane(4) with phenyl azide yielded a six-membered ring bearing a diboryl-triazene, whereby the B-B bond was ruptured by the insertion of an arylnitrene-like reactive intermediate. Both types of heterocycles feature unprecedented connectivity patterns and are very rare examples of boryl triazenes beyond the more common 1,2,3-triazolatoboranes. They are also the product of a unique type of aryl migration from a boron center to the phenyl azide γ-nitrogen center. Lastly, the substitution of 1,2-diaryl-1,2-dihalodiboranes(4) with azide groups, using trimethylsilyl azide as the transfer reagent, yielded boryl-tetrazaboroles and diboryldiazadiboretidines (as side-products), invoking the intermediacy of the first N-boryl-substituted iminoboranes, which are BN isosteres of monoborylated alkynes. The synthetic results are complemented with mechanistic proposals derived from quantum-chemical calculations.

Synthesis and characterization of 1,2,3-triazoles-linked urea hybrid sensor for selective sensing of fluoride ion

Two urea-linked 1,2,3-triazole based sensors (5a and 5b) have been synthesized by 1,3-dipolar cycloaddition between 1-(4-fluorophenyl)-3-(prop-2-yn-1-yl)urea (2) and phenyl azides (4a-4b) via copper(I)-catalyzed click reaction. The synthesized sensors 5a and 5b have been evaluated for their sensing ability towards anions (F−, Br−, Cl−, I−, H2PO4− and AcO−) and cations (Cu2+, Zn2+, Ca2+, Co2+, Cd2+, Hg2+, Pb2+ and Ni2+) through UV–Visible, fluorescence and NMR spectral techniques. It was observed that sensor 5a exhibited selective sensing for F− ion with a bathochromic shift in absorption spectrum and showed fluorescence “turn-on” behaviour in the emission spectroscopy. The UV–Visible experiments exhibited that 5a interact with F− ion with a stability constant (K) of 2.058 × 104 M−1 and detection limit of 5a for F− ions was found to be 65.76 ± 0.45 μM. Furthermore, these results were also supported by density functional theory (DFT) calculations.

Site-Specific Protein Photochemical Covalent Attachment to Carbon Nanotube Side Walls and Its Electronic Impact on Single Molecule Function.

Functional integration of proteins with carbon-based nanomaterials such as nanotubes holds great promise in emerging electronic and optoelectronic applications. Control over protein attachment poses a major challenge for consistent and useful device fabrication, especially when utilizing single/few molecule properties. Here, we exploit genetically encoded phenyl azide photochemistry to define the direct covalent attachment of four different proteins, including the fluorescent protein GFP and a β-lactamase binding protein (BBP), to carbon nanotube side walls. AFM showed that on attachment BBP could still recognize and bind additional protein components. Single molecule fluorescence revealed that on attachment to SWCNTs function was retained and there was feedback to GFP in terms of fluorescence intensity and improved resistance to photobleaching; GFP is fluorescent for much longer on attachment. The site of attachment proved important in terms of electronic impact on GFP function, with the attachment site furthest from the chromophore having the larger effect on fluorescence. Our approach provides a versatile and general method for generating intimate protein-CNT hybrid bioconjugates. It can be potentially applied to any protein of choice; the attachment position and thus interface characteristics with the CNT can easily be changed by simply placing the phenyl azide chemistry at different residues by gene mutagenesis. Thus, our approach will allow consistent construction and modulate functional coupling through changing the protein attachment position.

Conformer-Specific Heavy-Atom Tunneling in the Rearrangement of Benzazirines to Ketenimines.

5-Methoxy-2H-benzazirine was prepared via irradiation of the corresponding phenyl azide, isolated in an argon matrix at cryogenic temperatures. It undergoes ring expansion to the corresponding ketenimine in the dark at T < 30 K despite a calculated activation barrier of 4.9 kcal mol-1 [B3LYP/6-311++G(d,p)]. Since this rearrangement proceeds with a rate constant in the order of 10-4 s-1, exhibiting only a shallow temperature dependence, the results are interpreted in terms of heavy-atom tunneling. Of the four isomeric benzazirines resulting from the initial photolysis, only one can be observed to rearrange; this conformer specificity is explained by the other potentially observable rearrangements being either too fast or too slow to be detected due to the differences in heights and widths of their respective activation barriers.

TMSBr-Promoted Cascade Cyclization of ortho-Propynol Phenyl Azides for the Synthesis of 4-Bromo Quinolines and Its Applications.

Difficult-to-access 4-bromo quinolines are constructed directly from easily prepared ortho-propynol phenyl azides using TMSBr as acid-promoter. The cascade transformation performs smoothly to generate desired products in moderate to excellent yields with good functional groups compatibility. Notably, TMSBr not only acted as an acid-promoter to initiate the reaction, and also as a nucleophile. In addition, 4-bromo quinolines as key intermediates could further undergo the coupling reactions or nucleophilic reactions to provide a variety of functionalized compounds with molecular diversity at C4 position of quinolines.

Photolysis and Pyrolysis of Phenyltetrazoles: Formation of Phenylcarbodiimide, N‐Phenylnitrile Imine, Phenylnitrene, Indazole, and Fulvenallene

Photolysis of 1‐phenyltetrazole 2b at either 193 or 266 nm in a Ne matrix as well as flash vacuum pyrolysis (FVP) of the same compound with isolation of the products in Ne matrix generate phenylcarbodiimide PhN=C=NH 6 very efficiently as the principal product in an almost pure state. Minor amounts of phenyl azide 8 and 1‐azacyclohepta‐1,2,4,6‐tetraene 10, the product of ring expansion of phenylnitrene, are also formed, and the amounts of both substances increase as a function of photolysis time. The photolysis of 2‐phenyltetrazole 1b in a Ne matrix at 266 nm for 0.5 min generates the allenic N‐phenylnitrile imine PhN=N(+)=CH(–) 3b, absorbing strongly and cleanly at 2021 cm–1 in the IR spectrum. At longer photolysis times peaks ascribed to phenyl azide, phenylnitrene, 1‐azacycloheptatetraene, and phenylcarbodiimide 6 become prominent. FVP of 2‐phenyltetrazole yields indazole 15 as the major product together with a small amount of phenylcarbodiimide 6. Indazole formation is ascribed to cyclization of the nitrile imine in the ground state. It is not formed on FVP of 1‐phenyltetrazole in agreement with the computational result that the thermodynamically most favourable path for rearrangement of the putative N‐phenylimidoylnitrene 5b yields phenylcarbodiimide 6 rather than phenylnitrile imine 3b. Further pyrolysis of indazole affords a minor yield of fulvenallene 18.

Conservation of El-Sayed's Rules in the Photolysis of Phenyl Azide: Two Independent Decomposition Doorways for Alternate Direct Formation of Triplet and Singlet Phenylnitrene.

In the present work, we demonstrate that the formation of triplet and singlet phenylnitrene, when arises from the photodissociation of phenyl azide, fulfills El-Sayed's rules or the electronic angular momentum conservation law. It is shown that the singlet-triplet inversion of phenylnitrene via the vibronic coupling mechanism is not an effective process. In contrast, it is found that there exist two independent dissociation channels that yield alternatively singlet and triplet phenylnitrene. Therefore, a proposed mechanism that violates the angular momentum low is avoided. The clue of the photoreaction lies in the conjunction (energetic and spatial) of two crossing points in a very narrow region of the multidimensional space: (i) an intersystem crossing (ISC1) and (ii) a conical intersection (CI1). The geometrical separation between these two crossing geometries is only 0.016 Å measured in Cartesian coordinates, and the respective energy difference is 2 kcal/mol. This work has been performed by application of the complete active space self-consistent field and multiconfigurational second-order perturbation method.

1, 3-Dipolar cycloaddition reactions of selected 1,3-dipoles with 7-isopropylidenenorbornadiene and follow-up thermolytic cleavage: A computational study

The mechanism, regio-, stereo-, and enantio-selectivities of the 1,3-dipolar cycloaddition reactions of 7-isopropylidenenorbornadiene (DENBD) with nitrones and azides to form pharmaceutically relevant isoxazolidine and triazole analogues have been studied computationally at the M06/6-31G(d), 6-31G(d,p), 6-311G(d,p), 6–311++G(d,p) and M06-2X/6-31G(d) levels of theory. In the reactions of DENBD with phenyl nitrones, the cycloaddition steps have low activation barriers, with the highest being 16 kcal/mol; and the Diels-Alder cycloreversion steps have generally high barriers, with the lowest being 20 kcal/mol, suggesting that the isolable products in these reactions are the bicyclic isoxazolidine cycloadducts and not the thermolytic products. This is in contrast to the reactions of DENBD with phenyl azide where the isolable products are predicted to be the thermolytic products since the Diels-Alder cycloreversion steps had relatively lower activation barriers. Electron-donating substituents on the dipolarophile substrate favour attack of the nitrone on the least hindered side of the DENBD substrate while electron-withdrawing substituents on the dipolarophile substrate favour attack on the more hindered side of the DENBD, indicating that site-selectivity is affected by nature of substituents. Global reactivity indices calculations are in good agreement with the activation barriers obtained. Analysis of the electrophilic (PK+) and nucleophilic (PK−) Parr functions at the reactive centres reveal that the cycloaddition occurs between atoms with the largest Mulliken and NBO atomic spin densities which agrees well with the energetic trends and the experimental product outcomes.

Photosensitive Hydrogel Creates Favorable Biologic Niches to Promote Spinal Cord Injury Repair.

Photochemistry is considered to be a promising strategy for hydrogels to mimic the complex and dynamic properties of natural extracellular matrix. However, it is seldom applied in 3D tissue engineering and regenerative medicine due to the attenuation of light. In this study, phenyl azide photchemistry and optical fiber technology are first used to localize adhesive protein on the inner surface of the nerve guidance conduit in a 3D hydrogel scaffold. In vitro coculture assay of neural stem cells (NSCs) shows that photoimmobilization of collagen significantly improves the adhesion and survival of NSCs in the conduit, and exhibits synergistic effect with the sustainable release of growth factor. After implantation in transected spinal cord, the optimized hydrogel scaffold is found to improve the locomotion recovery of rats 12 weeks after spinal cord injury (SCI). Histological analysis suggests that the designed hydrogel scaffold provides a favorable biological niche for neuronal regeneration, thus producing directional neuron tissue and promoting the repair of SCI. This study demonstrates a promising hydrogel scaffold for SCI repair and provides the first understanding of the photoimmobilization of adhesive protein in a 3D hydrogel conduit concerning its functions on spinal cord tissue restoration.

Tetramethylrhodamine is an essential scaffold of azide probe in detecting cellular acrolein.

Tetramethylrhodamine (TAMRA)-phenyl azide is a chemical probe used to detect intracellular acrolein directly in live cells. Herein, we demonstrated that TAMRA is the optimum fluorophore for the probe. TAMRA-phenyl azide was used to reveal that high levels of acrolein are generated in a variety of breast cancer cells, regardless of the tumor subtype. These findings corroborate the analysis presented in our previous report, in which TAMRA-phenyl azide was used to label breast cancer tissues resected from breast cancer patients. Because high levels of acrolein were generated in all cancer cell types, we believe that acrolein detection may be useful as a general method for labeling cancerous tissues.

Reactions of Organic Azides with Half‐sandwich Complexes of Iridium: Preparation of Mono‐ and Bis(imine) Derivatives

Imine complexes [IrCl(η5‐C5Me5){κ1‐NH=C(H)Ar}{P(OR)3}]BPh4 (1, 2) (Ar = C6H5, 4‐CH3C6H4; R = Me, Et) were prepared by allowing chloro complexes [IrCl2(η5‐C5Me5){P(OR)3}] to react with benzyl azides ArCH2N3. Bis(imine) complexes [Ir(η5‐C5Me5){κ1‐NH=C(H)Ar}2{P(OR)3}](BPh4)2 (3, 4) were also prepared by reacting [IrCl2(η5‐C5Me5){P(OR)3}] first with AgOTf and then with benzyl azide. Depending on the experimental conditions, treatment of the dinuclear complex [IrCl2(η5‐C5Me5)]2 with benzyl azide yielded mono‐ [IrCl2(η5‐C5Me5){κ1‐NH=C(H)Ar}] (5) and bis‐[IrCl(η5‐C5Me5){κ1‐NH=C(H)Ar}2]BPh4 (6) imine derivatives. In contrast, treatment of chloro complexes [IrCl2(η5‐C5Me5){P(OR)3}] with phenyl azide C6H5N3 gave amine derivatives [IrCl(η5‐C5Me5)(C6H5NH2){P(OR)3}]BPh4 (7, 8). The complexes were characterized spectroscopically (IR, NMR) and by X‐ray crystal structure determination of [IrCl(η5‐C5Me5){κ1‐NH=C(H)C6H4‐4‐CH3}{P(OEt)3}]BPh4 (2b).

Ruthenium(II)-cored supramolecular organic framework-mediated recyclable visible light photoreduction of azides to amines and cascade formation of lactams

Ru(bpy)3]2+-cored supramolecular organic framework SMOF-1, assembled from a [Ru(bpy)3]2+-derived hexaarmed molecule and cucurbit[8]uril, has been demonstrated to heterogeneously catalyze visible light-induced reduction of phenyl, benzyl, 2-phenylethyl and 3-phenylpropyl azides in acetonitrile to produce the corresponding amines in good to high yields. For the last two kinds of azides that bear a CO2Me group at the para-position of the benzene ring, cascade reactions take place to generate the corresponding lactams in high yields. Compared with homogeneous control [Ru(bpy)3]Cl2, SMOF-1 exhibits remarkably increased photocatalysis activity as a result of synergistic effect of the [Ru(bpy)3]2+ units that form cubic cages to host the azide molecules and related intermediates. Moreover, SMOF-1 displays high recyclability and considerable photocatalysis activity after 3 to 12 runs.

Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H37Rv inhibitors besides antimicrobial activity

Quinazolin-4-ones linked to 1,2,3-triazol (10) were identified as inhibitors of the bisphosphonate BPH-700 transcriptional factor from a high throughput screen. A series of 1,4-disubstituted triazoles (10a–j) were synthesized by the Cu-catalyzed azide-alkyne cyclo addition of 5-methoxy-2-nitro-4-(prop-2-yn-1-yloxy) benzamide (6) with various substituted azido benzenes (7) in the presence of CuSO4 under aerobic conditions followed by click reaction with substituted aldehydes. The target compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv by Broth micro dilution method using Lowenstein Jensen medium (LJ) (MIC < 9 μg/mL). Majority of the compounds 10b, 10d, 10e, 10i and 10j displayed good antitubercular activity with MIC 7–11 μg/mL. Further, 10e exhibited a promising inhibition with MIC 7 μg/mL, compared to the reference drug Rifampicin. Docking studies have been performed to understand the interactions between the synthesized compounds and the active site of pantothenate synthetase Mycobacterium tuberculosis H37Rv organism. The study revealed that the target compounds showed good affinity toward the protein when compared to the standard drug Pefloxacin. Further, 10b was found to interact with three amino acids, viz., Gln92, Arg200, Ser196, as evidenced by the large interaction energy (ΔG = −8.16 kcal/mol). Besides the above, the synthesized quinazolinone triazoles 10a–j were evaluated for their antibacterial activities against a panel of Gram +ve and Gram –ve bacteria. Among them 10a, 10e, 10 h and 10j showed promising broad spectrum antibacterial activity with inhibition in the range of 19–33-mm diameter of inhibition zone (DIZ).