Diazonium Research Articles

Aryl diazonium salts and benzene derivatives bearing two electron-donor substituents: chemical and mechanistic behaviours.

The reaction between benzene derivatives 1-4 and p-substituted benzenediazonium tetrafluoroborates 5a-c provided novel azo-coupling products in high yields under mild conditions. The monitoring of the reaction progress using 1H-NMR provided mechanistic information on both the relative reactivity of the reagents and the possibility to detect novel reaction intermediates.

Iodine-mediated oxidative triple functionalization of indolines with azoles and diazonium salts.

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C-H functionalization to yield the indole derivatives.

Multi-substituted trifluoromethyl alkene construction via gold-catalyzed fluoroarylation of gem-difluoroallenes.

An unprecedented fluoroarylation of 1,1-difluoroallenes with a cost-effective nucleophilic fluoride reagent and aryldiazonium salts is reported. This visible light promoted gold-catalyzed reaction allows a stereo- and regioselective incorporation of both the fluorine atom and aryl group, enabling a straightforward construction of multi-substituted trifluoromethyl alkenes. Under the mild reaction conditions, a nice tolerance of diverse functional groups is achieved. The high regioselectivity for fluorine-incorporation is rationalized by considering the thermodynamic driving force of trifluoromethyl group formation, whereas the counterintuitive stereoselectivity that aryl is installed on the side of the bulkier γ-substituent is interpreted by alleviating the increasing 1,3-allylic interaction in the gold-coordinated allene intermediate en route to the product.

Coerulein B: a water-soluble and water-compatible near-infrared photoredox catalyst.

The recent expansion of photoredox catalysis into chemical biology has underscored the importance of photochemistry, attracting the attention of many researchers. On the other hand, as conventional photoredox catalysts were developed for organic synthesis, there is a necessity to develop biocompatible photoredox catalysts. Here, we show a water-soluble and water-compatible near-infrared (NIR) photoredox catalyst, coerulein B (CB). CB is a water-soluble molecule with a slightly twisted molecular structure, and its anionic species (CB-) exhibits NIR absorption and emission. We demonstrated that CB works as a water-compatible photoredox catalyst in the coupling reaction of pyridine hydrochloride and aryldiazonium salt. These results indicate that CB is one of the promising candidates for photocatalysts used in biological reactions.

Covalent functionalization by using blue light activated radicals: on the reaction mechanisms of arylazo sulfone binding on graphene.

Covalent functionalization of graphene presents a pivotal strategy to enhance its surface properties and overcome inherent chemical inertness. While diazonium salts have been extensively utilized for this purpose, their limitations necessitate exploration of alternative approaches. Arylazo sulfones, such as diazonium salt derivatives serving as chromophores, offer a promising solution, enabling photochemical reactions under visible light. Here, we propose a novel method for rapid covalent photofunctionalization of chemical vapor deposition (CVD) graphene on copper substrates using arylazo sulfones. The generation of aryl radicals - chlorobenzene in this case - was achieved through blue light LED irradiation of 4-chlorophenylazo methyl sulfone solution in acetonitrile. Efficient surface covalent modification of graphene was verified by observing (i) the photogeneration of radicals with a decrease in the π-π* band absorbance and an increase in the n-π* of arylazosulfone solution by UV-Vis spectroscopy; (ii) an increase in C sp3 defects on graphene from the Raman D band, the Auger C KLL signal and graphene C 1s X-ray photoelectron spectroscopy (XPS); and (iii) the presence of the chlorobenzene XPS Cl 2p signal. The aryl radical generation was enhanced by the copper substrate during irradiation, with a possible double path reaction mechanism. This approach highlights the versatility of arylazo sulfones in covalently patterning graphene surfaces, thus unlocking opportunities by overcoming the current approach consisting of the deposition of resist materials with successive cycles of lithography and electrochemistry.

Synthesis and application of well-defined [Ph4P]+[Cu(CF2CF3)2]- complex as a versatile pentafluoroethylating reagent.

We herein describe the preparation and application of a new bispentafluoroethylated organocuprate [Ph4P]+[Cu(CF2CF3)2]-. This complex has demonstrated a remarkable range of reactivities towards carboxylic acids, diazonium salts, organic halides, boronic esters, terminal alkynes and (hetero)arenes as a versatile pentafluoroethylating reagent. The construction of C(sp3)-/C(sp2)-/C(sp)-CF2CF3 bonds can therefore be achieved using a single reagent.

Discovery and development of tyrosine-click (Y-click) reaction for the site-selective labelling of proteins.

With the versatile utility of bio-conjugated peptides and proteins in the fields of agriculture, food, cosmetics and pharmaceutical industry, the design of smart protocols to conjugate and modulate biomolecules becomes highly desirable. During this process, the most important consideration for biochemists is the retention of configurational integrity of the biomolecules. Moreover, this type of bioconjugation of peptide and protein becomes frivolous if the reaction is not performed with precise amino acid residues. Hence, chemo-selective, as well as site-selective reactions, that are biocompatible and possess an appropriate level of reactivity are necessary. Based on click chemistry, there are so many tyrosine (Y) conjugation strategies, such as sulfur-fluoride exchange (SuFEx), sulfur-triazole exchange (SuTEx), coupling with π-allyl palladium complexes, diazonium salts, diazodicarboxyamide-based reagents etc. Among these techniques, diazodicarboxyamide-based Y-conjugation, which is commonly known as the "tyrosine-click (Y-click) reaction", has met the expectations of synthetic and biochemists for the tyrosine-specific functionalization of biomolecules. Over the past one and a half decades, significant progress has been made in the classical organic synthesis approach, as well as its biochemical, photochemical, and electrochemical variants. Despite such progress and increasing importance, the Y-click reaction has not been reviewed to document variations in its methodology, applications, and broad utility. The present article aims to provide a summary of the approaches for the modulation of biomolecules at the hotspot of tyrosine residue by employing the Y-click reaction. The article also highlights its application for the mapping of proteins, imaging of living cells, and in the fields of analytical and medicinal chemistry.

Multipodal Au-C grafting of calix[4]arene molecules on gold nanorods.

The interface robustness and spatial arrangement of functional molecules on metallic nanomaterials play a key part in the potential applications of functional nano-objects. The design of mechanically stable and electronically coupled attachments with the underlying metal is essential to bring specific desirable properties to the resulting hybrid materials. In this context, rigid multipodal platforms constitute a unique opportunity for the controllable grafting of functionality. Herein, we provide for the first time an in-depth description of the interface between gold nanorods and a chemically-grafted multipodal platform based on diazonium salts. Thanks to Raman and X-ray photoelectron spectroscopies and theoretical modeling, we deliver insights on the structural and electronic properties of the hybrid material. More importantly, it allows for the accurate assignment of Raman bands. The combination of experimental and theoretical results establishes the formation of four carbon-gold anchors for the calix[4]arene macrocycle leading to the exceptional stability of the functionalized nano-objects. Our results lay the foundations for the future design of robust and versatile platforms.

Visible light induced cooperative carbonylation and (hetero)aryl migration: synthesis of multi-carbonyl compounds.

Carbonylative transformation represents one of the most straightforward procedures for the synthesis of carbonyl-containing compounds. However, the carbonylative procedure toward 1,4-diketones is still limited which are key moieties with potent applications in various areas. Herein, we report a new strategy for the synthesis of multi-carbonyl compounds containing a 1,4-diketone skeleton through remote heteroaryl migration of traditionally restricted 1,3-migratory substrates utilizing carbon monoxide (CO) as the C1 synthon and diazonium compounds as the starting material.

Patterned organic layers on gold surfaces prepared by electro-grafting of photolabile-protected aryl diazonium salts

Direct photolithography of organic layers deposited via aryl diazonium electrografting by introduction of a photolabile protecting group.

A chemoselective hydroxycarbonylation and 13C-labeling of aryl diazonium salts using formic acid as C-1 source

We report a one-pot synthesis of aryl carboxylic acids utilizing HCOOH as a CO surrogate with low Pd-catalyst loading. This operationally simple and scalable method does not require a high-pressure...

Synthesis, molecular docking study, and biological evaluation and of new thiadiazole and thiazole derivatives incorporating isoindoline-1,3-dione moiety as anticancer and antimicrobial agents

To highlight the importance of thiazole and thiadiazole derivatives in the progression of cancer and microbial treatments and to aid in drug design, we have synthesized a new series of 1,3,4-thiadiazole and 1,3-thiazole derivatives. These were created by a two-step reaction process: initially, 2-(4-(2-bromoacetyl)phenyl)isoindoline-1,3-dione was reacted with potassium thiocyanate, and then the resulting thiocyanate intermediate was coupled with aryl diazonium salts to produce iminothiadiazole derivatives. These derivatives served as crucial intermediates for further synthesizing a range of thiadiazole derivatives using different reagents. Additionally, treating 2-(4-(2-bromoacetyl) phenyl)isoindoline-1,3-dione with thiourea resulted in aminothiazole derivatives. These were further coupled with arenediazonium chloride to form 5-arylazoaminothiazole derivatives. All the synthesised compounds were characterised using IR, 1H NMR and 13C NMR spectrum data, as well as physical data. The assessment of the synthesized compounds on the HCT-116 human colon cancer cell line has yielded promising results. Specifically, compounds 3a, 3b, 4b, 5b, 6b, and 9b have shown noteworthy efficacy, suggesting their potential as anticancer agents. These compounds have demonstrated a greater potency compared to the standard drug, doxorubicin, highlighting their significance in cancer treatment research. The study assessed the activity of various newly synthesized compounds against diverse microorganisms, including bacteria and fungi. Notably, two of these compounds, specifically 4b and 7b, exhibited significant efficacy against both gram-positive and gram-negative bacteria, surpassing the performance of a standard antibacterial reference agent. Furthermore, molecular docking of new products revealed interactions with enzyme binding sites, aligning with in vitro findings. Additionally, in-silico studies confirmed their favourable oral bioavailability through ADME profiling.

Z-selective radical difunctionalization of aromatic alkynes: synthesis of multi-substituted triarylethenes.

An efficient method for the radical difunctionalization of aromatic alkynes has been developed, resulting in the synthesis of a range of valuable triarylethenes. This approach utilizes strategically designed aryldiazonium salts with tertiary alcohol substitution as bifunctional reagents, along with cost-effective cuprous chloride as a catalyst. The method demonstrates remarkable Z-selectivity and is capable of gram-scale preparation. Additionally, a novel spin-trapping reagent has been developed based on the synthesized product.

An efficient ratiometric fluorescence and colorimetric dual-mode probe for convenient determination of nitrite in real samples and E. coli.

Developing an effective and convenient nitrite detection method is indispensable in food safety, environmental monitoring, clinical diagnosis of diseases, and many other areas. Herein, a dicyanoisophorone derivative, TMN-NH2 with large Stokes shift and near-infrared (NIR) emission, was proposed as a ratiometric fluorescence and colorimetric dual-mode probe for the rapid determination of NO2- in acidic media, showing excellent selectivity and high sensitivity. The sensing mechanism is based on the diazotization of TMN-NH2 with NO2- and subsequent diazonium salt hydrolysis to form a hydroxyl-substituted product (TMN-OH). Under the optimized conditions of reaction and detection, a new quantitative analysis method based on TMN-NH2 was established for NO2- detection, exhibiting good linear relationships to NO2- in the range of 0.5 to 15 μM with practical detection limits of 26.6 nM and 17.6 nM for the colorimetric and fluorescent readout, respectively. The quantitative detection of NO2- in real samples demonstrated satisfactory recoveries and repeatability. Moreover, TMN-NH2 was successfully applied for monitoring NO2- in Escherichia coli by confocal fluorescence imaging.

A novel chalcone compound as a reagent for the validation of pharmaceutical cefotaxime sodium preparations

This paper reports the synthesis of a new heterocyclic compound, 2,7-dicloropyrido[2,3-g]quinoline-3,8-dicarbaldehyde, from p-phenylene diamine by converting p-acetanilide (1) and reacting with Vilsmeier-Haack reagent (2). Chalcone(3) is produced when two moles of 2-acetyl naphthalene respond with the two carbaldehydes in compound (2). This chalcone serves as a reagent for quantifying amino group-containing pharmaceutical compounds. At the same time, a sensitive spectrophotometric technique has been created and used in pharmaceutical preparations to measure cefotaxime sodium by diazotizing and coupling with chalcone reagent. The recommended method diazotizes the medicinal molecule with sodium nitrite in an acidic solution to form the diazonium salt. This salt is combined with Chalcone reagent in an essential medium to create a stable and colorful azo dye soluble in water. Maximum absorption of the product is shown at 406 nm. Throughout the concentration range of 0.5–30 µg/ml, Beer's law was followed. The M absorptivity was (18381.44) liters mol-1. cm-1, the average recovery rate was 100.48 percent, and the relative standard deviation was less than 0.9 %. Injection-ready pharmaceutical preparations were the focus of the methodology.

Development of Spectrophotometric Method for The Determination of Mesalazine as Pure Form and in Tablets

This method involves development of a highly sensitive spectrophotometric procedure to estimate mesalazine as pure substance and in the tablets. This particular procedure was focused on the diazotization of mesalazine with an excess quantity of sodium nitrite (NaNO2) in an acid medium using HCl solution to produce a corresponding diazonium compound which reacts with 8-hydroxyquinoline reagent in an alkaline solution of NaOH to yield read-orange azo dye which is soluble in water and showed maximum absorption peak at the wavelength of 500 nm against the blank solution. The calibration graph was linear and compatible to Beer's law over the concentration range from 0.25 to 12.5 μg/ml with an exceptional determination coefficient (R2= 0.9994) and apparent molar absorptivity 2.88 × 104 L.mol-1cm-1. The limits of detection (LOD) and quantitation (LOQ) were premeditated and found to be 0.2023 and 0.6524 μg/ml, correspondingly. A relative error percent (accuracy) and the relative standard deviation (RSD%) was also calculated and found to be in the range -3.84% - 2.70%, and 0.17% - 1.94%, correspondingly. No interferences were observed from other ingredients that may be exist in the tablets. The stoichiometry of the resulting azo dye has been examined and the experimental results revealed that the mole ratio of mesalazine to 8-hydroxyquinoline is 1:1. The advised procedure was successfully applied for the determination of mesalazine in its pharmaceutical form (tablets).

An efficient synthesis, characterization, antimicrobial and anticancer activities of azo dyes derived from eugenol

A new series of azo dyes of the naturally occurring phenol i.e., eugenol (4-allyl-2-methoxyphenol) was produced by the conventional method. For the synthesis of azo compounds, diazonium salts were coupled with eugenol. Six substituted aryl-azo-eugenol derivatives (EU (a) to EU (f)) were synthesized and confirmed their structures with 1H NMR,13C NMR, FT-IR and Mass spectroscopy. All newly synthesized azo dyes of eugenol were evaluated for their in vitro antibacterial activity against S. aureus, S. pyogenus, E. coli, P. aeruginosa strains and in vitro antifungal activity against C. albicans, A. niger and A. clavatus strains by using micro broth dilution method. The results indicate that the synthesized azo dyes of eugenol display variable inhibitory effects on the growth of bacterial and fungal strains. Further, all compounds were evaluated for their anticancer activity against human breast cancer cell lines MDA-MB-241, the compound EU(d) displays excellent anticancer activity.

Green and Low-Cost Synthesis of Thermally Stable Cation-Exchange Resin-Supported Diazonium Salt: An Example of Weakly Basic p-Nitroaniline Diazotization

Green and Low-Cost Synthesis of Thermally Stable Cation-Exchange Resin-Supported Diazonium Salt: An Example of Weakly Basic <i>p</i>-Nitroaniline Diazotization

Controlled Surface Functionalization Using Aryldiazonium Salts for the Development of Aptasensing Platforms

It is well known that both the aptamer surface density and surface chemistry can have a strong influence on the analytical performance of aptasensors based on target-induced conformational changes1. In this context, we report here an improved protocol for obtaining aptasensing platforms which allows fine-tuning the DNA aptamer surface coverage. First, glassy carbon substrates were functionalized with ethynylphenyl groups through the electrochemical reduction of silyl-protected ethynylphenyl diazonium tetrafluoroborates followed by deprotection with tetrabutylammonium fluoride2. The successful removal of the protecting groups (triisopropylsilyl-, triphenylsilyl- and tris(biphen-4-yl)silyl-) was confirmed by X-ray photoelectron spectroscopy and cyclic voltammetry in the presence of Fe(CN)6 3-/4- as soluble redox probe. Following “click” post-modification with suitable derivatization reagents, the surface coverage with ethynylphenyl groups was assessed using complementary techniques such as XPS, cyclic voltammetry and chronocoulometry. For example, the F/C surface ratio of substrates derivatized with 1-(2,2,2-trifluoroethoxy)-6-azidohexane provided an indication of the functionalization degree, and the integration of Fc/Fc+ voltammetric peaks for substrates modified with N-(6-azidohexyl)ferrocenecarboxamide allowed a quantitative determination of the surface coverage. Both techniques showed a good correlation between the protective group size and the surface coverage with alkyne groups. Likewise, we observed a similar trend for substrates derivatized with azide-modified oligonucleotides, where the surface packing density was determined based on the chronocoulometric response of Ru(NH3)6 3+, a cationic redox probe which binds with the negatively charged phosphate groups from the oligonucleotide backbone. As proof of concept, we further developed an electrochemical molecular beacon aptasensor employing a ferrocene-labeled quinine aptamer. We demonstrate that the aptamer surface density, and ultimately the analytical performance of molecular beacon aptasensors, can be effectively fine-tuned by employing silyl protecting groups of different sizes.Acknowledgements This work was supported by a grant from the Romanian Ministry of Education and Research, CNCS-UEFISCDI, project number PN-III-P4-ID-PCE-2020-2474, within PNCDI III. References Onaş, A. M., Dascălu, C., Raicopol, M. D. & Pilan, L. Critical Design Factors for Electrochemical Aptasensors Based on Target-Induced Conformational Changes: The Case of Small-Molecule Targets. Biosensors 12, (2022).Leroux, Y. R., Fei, H., Noël, J.-M. M., Roux, C. & Hapiot, P. Efficient covalent modification of a carbon surface: Use of a silyl protecting group to form an active monolayer. J. Am. Chem. Soc. 132, 14039–14041 (2010).

Diazonium salt as a versatile, efficient and mild catalyst for reductive aminations of carbonyls and syntheses of bis(indolyl)methanes

This study used aryl diazonium salts as catalysts to catalyze reductive aminations of carbonyls and the synthesis of bis (3-indolyl)methane derivatives. The catalytic system showed good tolerance to substituents in the substrate in these two reactions. The separation yields of reductive aminations range from moderate to excellent. The separation yield of the reaction for synthesizing bis(3-indolyl)methane derivatives ranges from good to excellent. Finally, we also explored the catalytic behavior of aryl diazonium salts in amination reduction reactions.