Diazonium Ion Research Articles

Synthesis and Study Biological Activity of Some New Substituted Thiazolidin-4-one Derivatives

The microwave (MW) method was used to create a series of new thiazolidin-4-one derivatives containing benzothiazole and azo groups. Azoaldehyde derivative A was synthesized via the coupling reaction of 2-aminobenzothiazole diazonium ions and 2-hydroxybenzaldehyde. The resultant azoaldehyde A was then subjected to condensation reactions with the primary aromatic amines using the MW method to give azoimines derivatives S1-S5. Finally, compounds S1-S5 were reacted with α-mercaptoacetic acid by the MW method to generate the thiazolidin-4-one derivatives T1-T5. The novel-produced compounds T1-T5 were identified by FT-IR, 1H NMR, and 13C NMR spectroscopy. The DPPH was used to determine the antioxidant activity of the novel-produced compounds T1-T5. The obtained results for T1 and T5 were excellent as antioxidants in comparison with ascorbic acid, while in the antibacterial study, it was discovered that T2, T3, and T5 were found to be more successful than Gentamycin as a control drug against Staphylococcus aureus in an antibacterial investigation, while T3 was found to be more effective than the reference drug against Escherichia coli.

Facile synthesis of Ti3C2Tx MXene nanosheets using aryl diazonium tetrafluoroborate for multiple applications

The development of an HF-free and environmentally benign method for etching the middle aluminum layer (Al) from the Ti3AlC2-MAX phase is a challenging task in titanium carbide (Ti3C2Tx) MXene synthesis. Herein, we designed a diazonium salt-based ultrasonic method to prepare MXene. We have explored 4-carboxy benzene diazonium tetrafluoroborate (4-CBDF) as a delaminating agent, which can dissolve the Al layer directly from the MAX phase. 4-carboxy benzene diazonium (4-CBD+) ion promotes the intercalation as well as exfoliation simultaneously during the etching of the MAX phase and directly results in Ti3C2Txnanosheets without undergoing any additional delamination process. Synthesized MXene nanosheets show excellent photothermal performance with a conversion efficiency of 59 %. This MXene-coated GC electrode exhibits the highest capacitance of 1133 F/g at a current density 1 A/g, which maintains a retention capacitance of 91% even after 10,000 GCD cycles. The present method provides a fundamental insight into the development of MXene-based next-generation photothermal materials and supercapacitors.

5-(Pyridin-3-yl)-3,4-dihydro-2H-furan-1-ium (NNKFI): a computational study of its physico-chemical properties.

Recent work on the diazonium ion metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKDI) suggests that 5-(pyridin-3-yl)-3,4-dihydro-2H-furan-1-ium (NNKFI) may form from NNKDI via an intramolecular reaction. NNKDI is an important carcinogen whose role as an alkylating agent has received significant attention. While there is some experimental evidence supporting NNKFI's production in vitro, it has not yet been directly observed. Little is known about NNKFI's structure and reactivity. We report the first in silico examination of this ion. Our study utilized Kohn-Sham density functional theory (B3LYP/6-311G**) and coupled cluster theory (CCSD/6-31G*) to produce energy-optimized structures, vibrational normal modes and molecular orbitals for NNKFI. To gain insight into the chemical properties of this species, we calculated electrostatic potential surfaces, natural population analysis charges and local Fukui indices. We report data and results for NNKFI's cis and trans conformers. Our work confirms C5 as the preferred site for nucleophilic attack in NNKFI. Stretching motions and predicted bond lengths near O1 are consistent with a somewhat weakened carbonyl structure in this ion. Partial charges, electrostatic potential surfaces and local Fukui indices reveal delocalization of cationic charge on the furanium moiety and notable carbocation character at C5.

Origins of Diastereoselectivity in the Addition of Enoxysilanes to Vinyl Diazonium Salts.

The addition of enoxysilanes to vinyl diazonium ions occurs with varying levels of diastereoselectivity. To understand the origins of the stereoselectivity, we studied these transformations using density functional theory (DFT) calculations. The selectivity stems from a stabilizing cation-π interaction that orients the nucleophile and the diazonium ion.

Quantum chemical calculations of nitrosamine activation and deactivation pathways for carcinogenicity risk assessment.

N-nitrosamines and nitrosamine drug substance related impurities (NDSRIs) became a critical topic for the development and safety of small molecule medicines following the withdrawal of various pharmaceutical products from the market. To assess the mutagenic and carcinogenic potential of different N-nitrosamines lacking robust carcinogenicity data, several approaches are in use including the published carcinogenic potency categorization approach (CPCA), the Enhanced Ames Test (EAT), in vivo mutagenicity studies as well as read-across to analogue molecules with robust carcinogenicity data. We employ quantum chemical calculations as a pivotal tool providing insights into the likelihood of reactive ion formation and subsequent DNA alkylation for a selection of molecules including e.g., carcinogenic N-nitrosopiperazine (NPZ), N-nitrosopiperidine (NPIP), together with N-nitrosodimethylamine (NDMA) as well as non-carcinogenic N-nitrosomethyl-tert-butylamine (NTBA) and bis (butan-2-yl) (nitros)amine (BBNA). In addition, a series of nitroso-methylaminopyridines is compared side-by-side. We draw comparisons between calculated reaction profiles for structures representing motifs common to NDSRIs and those of confirmed carcinogenic and non-carcinogenic molecules with in vivo data from cancer bioassays. Furthermore, our approach enables insights into reactivity and relative stability of intermediate species that can be formed upon activation of several nitrosamines. Most notably, we reveal consistent differences between the free energy profiles of carcinogenic and non-carcinogenic molecules. For the former, the intermediate diazonium ions mostly react, kinetically controlled, to the more stable DNA adducts and less to the water adducts via transition-states of similar heights. Non-carcinogenic molecules yield stable carbocations as intermediates that, thermodynamically controlled, more likely form the statistically preferred water adducts. In conclusion, our data confirm that quantum chemical calculations can contribute to a weight of evidence approach for the risk assessment of nitrosamines.

Synthesis, antibacterial and antibiofilm activity of new 1,2,3,5-tetrazine derivatives from coupling reactions of diazonium salt of 2-amino-6-nitrobenzothiazole with diverse substituted 2-aminobenzothiazole derivatives.

The coupling reaction of diazonium ion of 2-amino-6-nitrobenzothiazole at 0-5 °C with distinctly substituted 2-aminobenzothiazole derivatives produced new 1,2,3,5-tetrazine derivatives. It was found that diazotized 2-amino-6-nitrobenzo[d]thiazol reacts with the ring nitrogen atom of varyingly substituted 2-aminobenzothiazole derivatives to yield tetrazine nucleus. The benzene ring of benzothiazole bearing electron donor group and annelated to the tetrazine was further substituted in situ by other 6-nitrobenzo[d]thiazol-2-yl) diazinyl to yield the final product. The structure of the prepared compounds was elucidated using their physical, elemental, and spectroscopic data. The synthesized compounds were tested for their antimicrobial and antibiofilm activities against Staphylococcus aureus and Escherichia coli bacteria. Two of the synthesis tetrazine derivatives exhibited interesting antibiofilm potential.

Chemical Probes to Interrogate the Extreme Environment of Mosquito Larval Guts.

Mosquito control methods are vital to curtail the spread of life-threatening illnesses, such as dengue fever, malaria, and yellow fever. Vector control technologies must be selective to minimize deleterious effects on our ecosystem. Successful methods that control mosquito larva populations utilize the uniquely high alkaline nature of the midgut. Here, we present novel protected triazabutadienes (pTBD) that are deprotected under basic conditions of the larval midgut, releasing an aryl diazonium ion (ADI) that results in protein modification. The probes contain a bioorthogonal terminal alkyne handle, enabling a selective Cu-click reaction with an azidofluorophore for quantification by SDS PAGE and visualization using fluorescence microscopy. A control TBD, unable to release an ADI, did not label the midgut. We envision our chemical probes will aid in the development of new selective mosquito control methods, thus preventing the spread of mosquito-borne illnesses with minimal impact on other organisms in the ecosystem.

O-H Insertion of Hydrogenphosphate Derivatives and α-Diazo Compounds.

An efficient O-H insertion of hydrogenphosphate derivatives and α-diazo compounds has been developed to construct α-phosphoryloxy scaffolds. Diverse α-phosphoryloxy skeletons could be obtained under mild and catalyst-free conditions in good yields. The control experiments suggest a protonation and nucleophilic addition process of α-diazo compounds via a diazonium ion pair for this transformation.

Lewis acid mediated allylation of vinyl diazonium ions by allylstannanes.

The Lewis acid mediated reaction of allyltributylstannane compounds with β-hydroxy-α-diazo carbonyls gives β-allyl-α-diazo carbonyl products in good yields. This reaction proceeds via a vinyl diazonium ion intermediate which is intercepted by the allylstannane nucleophile. Importantly, the diazo functional group is retained over the course of the reaction to give diazo-containing scaffolds with increased molecular complexity. Methallyltrimethylsilane also serves as a functional allyl transfer reagent in this reaction.

A facile tert-butyl nitrite-assisted preparation of deamino graphitic carbon nitride (DA-gCN) as a photocatalyst for the C-H arylation of heteroarenes using anilines as radical source.

In pristine graphitic carbon nitride (g-CN), amino groups often function as structural defects that trap photogenerated charges, resulting in low photocatalytic activity as well as reaction with nitrite, aldehyde, etc., ensuing in poor product yield. Without significantly altering the optical characteristics, the removal of amino groups is necessary to increase the photocatalytic activity and structural stability of pristine g-CN. The deamino graphitic carbon nitride (DA-gCN-5) was prepared by tert-butyl nitrite (TBN)-treatment, characterized and used as a photocatalyst for the radical C-H arylation of heteroarenes using anilines as radical source. Indeed, the photophysical characteristics of DA-gCN-5 and those of pristine g-CN are very comparable, except that DA-gCN-5 has a fewer residual amino groups, higher crystallinity, and compressed structure with a different morphology. Moreover, DA-gCN-5-catalyzed C-H arylation reaction offers greater product yield in a shorter reaction time compared to that of pristine g-CN in the coupling between heteroarenes and the in situ generated aryl diazonium salts from anilines under visible light irradiation. The amino groups in pristine g-CN absorbed the TBN that was added to convert aniline into the appropriate diazonium ions during the reaction. As a result, deamino graphitic carbon nitride produced by chemical treatment has better photophysical properties and catalytic activity than pristine g-CN. Additionally, this is the first method that uses diazotization reaction for the preparation of deamino graphitic carbon nitride, as far as we are aware.

Revisiting the Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

N-Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation of the DNA-alkylating diazonium ion. Following up on the in-silico identification of thousands of nitrosamines that can potentially be derived from small molecule drugs and their known impurities described in a previous publication, we have now re-analyzed this dataset to apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with the 16th revision of their Q&A document for Marketing Authorization Holders. We find that the majority of potential nitrosamines from secondary amine precursors belongs to potency categories 4 and 5, corresponding to an acceptable daily intake of 1500 ng, whereas nitrosamines from tertiary amine precursors distribute more evenly among all categories, resulting in a substantial number of structures that are assigned the more challenging acceptable intakes of 18 ng/day and 100 ng/day for potency categories 1 and 2, respectively. However, the nitrosative dealkylation pathway for tertiary amine is generally far slower than the direct nitrosation on secondary amines, with a direct nitrosation mechanism suspected only for structures featuring electron-rich (hetero)aromatic substituents. This allows for greater focus towards those structures that require further review, and we demonstrate that their number is not substantial. In addition, we reflect on the nitrosamine risk posed by secondary amine API impurities and demonstrate that based on the ICH Q3A/B identification threshold unknown impurities may exist that could be transformed to relevant amounts of NA. We also demonstrate that the analytical sensitivity required for the quantification of high potency nitrosamines can be problematic especially for high dose APIs. In summary, the regulatory framework rolled out with the latest Q&A document represents a substantial improvement compared with the previous situation, but further refinement through interaction between manufacturers, regulators, not-for-profit and academic institutions will be required to ensure patient access to vital medicines without compromising safety.

Methylation of graphene (pristine and S-doped) by carcinogenic methane diazonium ion: a DFT study

ABSTRACT Herein, we aim to explore the efficiency of graphene in scavenging the carcinogenic methane diazonium ions (CH3N2 +) which are capable of methylating DNA and other biomolecules readily. Therefore, methylation of graphene (pristine and S-doped) by CH3N2 + was investigated theoretically using density functional theory. Our calculations show that graphene (both pristine and S-doped) can be readily methylated by CH3N2 +. However, as S-doped graphene exhibited better reactivity than pristine graphene, we believe that the former would act as a better scavenger for CH3N2 + than the latter one.

Color based spectrophotometric determination of vericiguat using diazo coupling reaction; assisted computational calculations

A novel spectrophotometric method aided by computational techniques has been developed to determine vericiguat, a soluble guanylate cyclase stimulator used for reducing the risk of heart failure and cardiovascular mortality. Using density functional theory calculations, 8-hydroxyquinoline was identified as the best coupling agent for the spectrophotometric determination of vericiguat. The method involves the creation of a red-colored chromogen by combining vericiguat with sodium nitrite to form a diazonium ion, which then reacts with 8-hydroxyquinoline. The resulting complex exhibits distinct absorption peaks at 515 nm. Various factors influencing the diazotization process were investigated, and the concentration range of 1–12 μg/mL vericiguat was found to adhere to Beer's law. Job's plot analysis revealed a 1:1 stoichiometric ratio between vericiguat and 8-hydroxyquinoline. This reaction formed the basis for determining vericiguat spectrophotometrically, both in its pure form and in pharmaceutical formulations. Additionally, an analytical greenness metric was employed to evaluate the environmental friendliness of the proposed procedure. The results demonstrated that the method aligns with established values of green analytical chemistry metrics.

Lewis-Acid-Catalyzed Oxa-Michael Addition to Give α-Diazo-β-alkoxy Carbonyls and Tetrahydro-3H-furo[3,4-c]pyrazoles.

The conjugate addition of alcohols to vinyl diazonium ions formed via Zn(OTf)2-catalysis gives α-diazo-β-alkoxy carbonyls. The diazo group is retained in this reaction, and this process is an efficient way to couple a reactive partner to the diazo fragment. As an example, we disclose that addition of allyl alcohols provides tetrahydro-3H-furo[3,4-c]pyrazoles via an addition/cycloaddition sequence. This two-step sequence provides good yields and good diastereoselectivity of these sterically hindered pyrazoline scaffolds with up to three quaternary centers and four stereogenic centers. These products can be elaborated to cyclopropane-fused tetrahydrofurans upon liberation of nitrogen. The reaction conditions are mild, operationally simple, and avoid the use of expensive transition metal catalysts.

Synthesis, characterization, and antibacterial activity of a new poly azo compound containing N-arylsuccinimid and dibenzobarrelene moieties

Abstract The present work describes the synthesis, characterization, and evaluation of the antibacterial activity of a new poly azo compound resulting from the coupling of a previously reported N-arylsuccinimid precursor 5 with the diazonium ion of aniline. This azo compound was characterized using its physical, elemental, and 1D and 2D spectroscopic data. The novel azo compound 7 (minimum inhibitory concentration [MIC] = 16–32 μg/mL) showed higher antibacterial activity than its precursor 5 (MIC = 32–64 μg/mL), although it was low compared to the reference drug ciprofloxacin (MIC = 0.5–4 μg/mL).

New protocol for functionalization of fullerene soot with dinitrobenzene groups from a non-diazonium resource

The nitrobenzene functionalized fullerene soot has been considered as a potentially energetic material. In our previous study, the in situ produced nitrobenzene diazonium ions have been used for the synthesis of 2-nitrobenzene, 4-nitrobenzene and 2,4-dinitrobenzene functionalized fullerene soot nanoparticles with moderate oxygen (14.91 wt%) and nitrogen (6.27 wt%) contents. In the present study, a new protocol for the functionalization of fullerene soot with 3,5-dinitrobenzene groups from a non-diazonium resource is reported. The functionalization of fullerene soot is performed through Ag(I)-catalyzed decarboxylative oxidation of 3,5-dinitrobenzoic acid (DNBA) under conventional heating or microwave irradiation. The effects of various parameters such as the oil bath temperature and the amounts of substrate (DNBA), catalyst (AgNO3) and oxidant (K2S2O8) on these reactions are evaluated. The synthesized compounds are characterized by FT-IR, Raman, XRD, SEM-EDX and elemental mapping analysis, FE-SEM and TEM along with particle size analysis, as well as TGA-DSC. The DSC thermograms of functionalized fullerene soot show a single exothermic peak attributed to the exothermic decomposition of 3,5-dinitrobenzene groups. Some of these compounds have up to 82.16 wt% oxygen and 6.10 wt% nitrogen contents. These findings are important for development of the energetic materials with improved oxygen content.

Study of Synthesis, Characterization, DFT, and In Vitro Biological Activity of Cu(II), Co(II), and Fe(II) Metal Complexes Based on Heterocyclic Azo Pyrazole Dye Ligand

A new azo dye ligand was synthesized by coupling 5-amino-3-methyl-1-phenylpyrazole with a diazonium ion of 2-amino-1-naphthalene sulfonic acid. Its Co(II), Fe(II), and Cu(II) complexes were also synthesized. This ligand and its complexes were characterized based on elemental analysis, IR, 1H NMR, UV-vis spectra, and thermogravimetric analysis. The data showed that the proposed complexes have an octahedral geometry around the central metal ion. The nonelectrolytic nature of the complexes was confirmed by molar conductance measurement. X-ray powder diffraction indicates that Co(II) and Fe(II) complexes are amorphous in nature, whereas the Cu(II) complex has crystalline and amorphous phases. The bond strength and molecular stability between the interaction of metal ions and the ligand were investigated by density functional theory (DFT). The in vitro antibacterial activity of the ligand and complexes was tested against two Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative bacteria (Escherichia coli and Neisseria gonorrhoeae) and a fungus (Candida albicans). The Cu(II) complex exhibited a high antimicrobial effect against all tested microorganisms. The DNA fragmentation percentage and cytotoxic activity against human liver cancer cells (HepG2) were evaluated. All tested compounds showed potential anticancer activity, and the Co(II) complex showed better activity results than the other tested compounds, with IC50 = 19.55 μg/mL.

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients.

The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence in all medicinal products. In the absence of rodent carcinogenicity data for novel N-nitrosamines derived from amine-containing APIs, a conservative class limit of 18 ng/day (based on the most carcinogenic N-nitrosamines) or the derivation of acceptable intakes (AIs) using structurally related surrogates with robust rodent carcinogenicity data is recommended. The guidance has implications for the pharmaceutical industry given the vast number of marketed amine-containing drugs. In this perspective, the rate-limiting step in N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation to yield DNA-reactive diazonium or carbonium ion intermediates, is discussed with reference to the selection of read-across analogs to derive AIs. Risk-mitigation strategies for managing putative N-nitrosamines in the preclinical discovery setting are also presented.

Green adherent spectrophotometric determination of molnupiravir based on computational calculations; application to a recently FDA-approved pharmaceutical dosage form

Molnupiravir is an oral antiviral drug developed to provide significant benefit in reducing hospitalizations or deaths in mild COVID-19. Integrated green computational spectrophotometric method was developed for the determination of molnupiravir. Theoretical calculations were performed to predict the best coupling agent for efficient diazo coupling of molnupiravir. The binding energy between molnupiravir and various phenolic coupling agents, α-naphthol, β-naphthol, 8-hydroxyquinoline, resorcinol, and phloroglucinol, was measured using Gaussian 03 software based on the density functional theory method and the basis set B3LYP/6-31G(d). The results showed that the interaction between molnupiravir and 8-hydroxyquinoline was higher than that of other phenolic coupling agents. The method described was based on the formation of a red colored chromogen by the diazo coupling of molnupiravir with sodium nitrite in acidic medium to form a diazonium ion coupled with 8-hydroxyquinoline. The absorption spectra showed maximum sharp peaks at 515 nm. The reaction conditions were optimized. Beer's law was followed over the concentration range of 1–12 μg/ml molnupiravir. Job's continuous variation method was developed and the stoichiometric ratio of molnupiravir to 8-hydroxyquinoline was determined to be 1:1. The described method was successfully applied to the determination of molnupiravir in pure form and in pharmaceutical dosage form. The results showed that the proposed method has minimal environmental impact compared to previous HPLC method.

Smartphone-based colorimetric determination of triclosan in aqueous samples after ultrasound assisted-dispersive liquid–liquid microextraction under optimized response surface method conditions

In the present study, a simple and low cost methodology based on ultrasonic assisted-dispersive liquid–liquid microextraction (UA-DLLME) followed by smartphone-based colorimetric measurement was introduced for the separation and determination of Triclosan (TCS) from contaminated waters. This method is based on the formation of an azo compound from the alkaline reaction of TCS with a diazonium ion, resulting from the reaction of sodium nitrite and p-sulfanilic acid in an acidic medium. The orange-brown color product was extracted into a low volume of organic phase by UA-DLLME method and RGB values were recorded with free Android app Color Grab. The effective parameters in this procedure, namely solution pH, p-sulfanilic acid and nitrite concentration, reaction time and volume of the extraction solvent were investigated and optimized by response surface methodology (RSM) based on a Box-Behnken design (BBD) model. Under optimum conditions, the calibration graph was linear in the range of 3.0 and 200 μg L-1 of TCS. The limit of detection (LOD) and limit of quantification (LOQ) were 0.8 and 2.7 μg L-1, respectively. The proposed method was successfullyused for the analyses of triclosan in several water and wastewater samples and satisfactory results were obtained.