Aromatic Chlorination Research Articles

N-Chlorosuccinimide: A Versatile Reagent in Organic Synthesis

N-Chlorosuccinimide (NCS) is a five-membered N-containing heterocyclic molecule. This is a versatile reagent and is successfully employed for different types of reactions. Initially, this was employed for chlorination only but soon became an excellent reagent for many reactions, including halocyclizations, functional group transformations, formation of carbon-carbon bonds, etc. This review article covers representative applications of NCS for aliphatic and aromatic chlorination, chlorination of atoms other than carbon, oxidation, and other reactions.

Dabco-catalysed selective chlorination of aromatics

In this report, we present a highly efficient aromatic chlorination that is catalysed by 1,4-diazabicyclo[2.2.2]octane (DABCO) with N-chlorosuccinimide (NCS) as the chloro source. The mild conditions, easy-availability and stability of the catalyst and reagents, as well as good functional-group tolerance, showed the approach to be a versatile protocol for the late-stage aromatic chlorination of complex natural products and drugs. A plausible catalytic mechanism was constructed through comprehensive computational studies.

Alkene versus Aryl Chlorination in Asymmetric Hypervalent Iodine Catalysis: A Case Study

AbstractHypervalent λ3-iodanes have become a prominent tool for halofunctionalizations of alkenes. Despite many examples of asymmetric fluorinations reported lately, the corresponding enantioselective chlorination reactions using iodoresorcinol-based catalysts are significantly less developed, with only one example known to date. Here, we show how competing aromatic chlorination of the iodoarene catalyst is a significant obstacle in these transformations, hinting towards a conceptual issue with this well-established catalyst class for enantioselective chlorinations. Consequently, the reaction conditions and the catalyst design must be adapted to facilitate an effective chirality transfer. Hence, attention should be paid when selecting the oxidizing agent, the stoichiometry, and careful reaction analysis must be conducted to identify the factual catalytically active species.

Selectfluor-mediated chlorination and fluorination of arenes: late stage functionalization of APIs and its biological effects.

By using APIs previously recovered from expired drugs, it is shown that Selectfluor can act as a reagent for operationally simple late-stage fluorination and chlorination of electron-rich arenes under mild reaction conditions. As shown in mechanistic experiments, aromatic fluorination thereby competes with chlorine-for-fluorine exchange on Selectfluor and subsequent aromatic chlorination, whereat the chloride ions may either be provided by the hydrochloride salt of the respective API or by triethylammonium chloride. Biological testing of the fluorinated or chlorinated APIs at adrenergic, dopaminergic, muscarinergic, opioid or serotoninergic receptors demonstrated that improved binding affinities can be achieved via this straightforward strategy.

Enhanced electrochemical chlorination of anisole in Fe2O3 nanoparticles integrating with crystal facet effect

Electrochemical aromatic chlorination reaction (E-ACR) represented by electrocatalytic chlorination of anisole (ANI) is a promising and economical strategy due to its mild reaction conditions and environmental friendliness. However, exploring advanced non-precious metals E-ACR electrocatalysts remains a great challenge. Herein, we synthesized Fe2O3-X nanoparticles (Fe2O3-X NPs, where X represented calcination temperature) integrating with crystal facet effect for efficiently electrochemical converting ANI into para-chloroanisole (4-CANI). Among them, Fe2O3-400 NPs shows significantly improved E-ACR catalytic activity, featured with average 48 % of Faradaic efficiency (FE) and maximum 73 % of selectivity of 4-CANI at 2.4 V. Analyses indicate that the performance of Fe2O3-X NPs is positively correlated with the intensity of (400) facet, and the (400) fact can optimize the adsorption of the *C6H5OCH3 and *C6H4OCH3 intermediates to improve conversion efficiency of 4-CANI. This work highlights the crystal facet‐performance relationship of catalysts for E-ACR and gives critical insights into the effect of crystal structure for nanomaterials on E-ACR.

Kinetic study on the activation of PhICl2 with Lewis bases for aromatic chlorination.

A study on the kinetics of the activation of PhICl2 using catalytic chloride or pyridine in electrophilic chlorination of arenes has been carried out. The results indicate that both catalysts induce the release of Cl2 from PhICl2 and that the Cl2 is the active reagent for chlorination in these reactions.

Simple and cost-efficient chlorination of electron deficient aromatics to provide templates for organogelation and fluoride sensing

This present work describes the synthesis of extremely electron-deficient novel nitroaromatic compounds from trinitrophenols using new synthetic methods and applying them to derive soft materials. Multi chlorination has been achieved at a single shot using phosphorus oxychloride in both cases. We have explored the mechanism of this new type of transformation using the DFT study. Compounds 2a-b have been successfully utilized to provide a template for organogelation using a non-gelator methyl ester of phenylalanine. Interaction leading towards the gel has also been investigated using the DFT study. Various aspects of this two-component gelation and fluoride mediated gel to sol transformation have been investigated. The fluoride sensing property of compound 2a has also been explored in the THF-water mixture. The yellow solution of compound 2a becomes reddish-brown in presence of fluoride ion. Using compound 2a aqueous fluoride can be detected down to 12.2 ppb level.

Effect of urea on chlorinated aromatics formation mediated by copper and iron species in combustion flue gas

Urea ((NH2)2CO) is widely applied to the reduction of NOX in modern full-scale solid waste incineration systems, but there is a lack of knowledge about how urea affects the formation and emission of Cl-aromatics. In this study, we investigated the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated polychlorinated naphthalenes (PCNs) via electrophilic chlorination and precursor pathway mediated by model fly ashes containing Cu and Fe species with or without urea addition. The results indicated that the addition of urea promoted the direct chlorination of parent aromatics over Cu (Ⅱ) chlorides and the coupling reaction of chlorophenols over Fe species, while suppressed the catalytic chlorination of parent aromatics over Fe (Ⅲ) chlorides and the coupling reaction of chlorophenols over Cu species. The diverse effects should be mainly attributed to the formation of complex salts containing NH3 and NH4+. The formation of complex salts of Fe chlorides and NH4Cl could hinder the oxidization of Fe chlorides, and thus maintain the high activity of Fe species for catalyzing the coupling reaction of chlorophenols. The formation of complex salts of Cu (Ⅱ) chloride and NH3 could prevent the chemical sorption of phenoxyl groups, and thus suppress the coupling reaction of chlorophenols. NH3 released from the thermal decomposition of urea could not only react with Cl2 to suppress the catalytic chlorination of aromatics, but also neutralize HCl to accelerate the direct chlorination of aromatics. In general, urea should act as inhibitor for suppressing the formation of Cl-aromatics in solid waste incineration systems.

Inhibition Effect and Mechanism of Thiourea on Electrophilic Chlorination of Aromatics in Combustion Flue Gas.

Thiourea can effectively inhibit the formation of highly toxic chlorinated aromatics in postcombustion zone. However, the inhibition mechanism was still not adequately understood. In this study, naphthalene was adopted as a model aromatic compound to investigate the inhibition effect and mechanism of thiourea on the formation of chlorinated aromatics via electrophilic chlorination over Cu and Fe chlorides. Thiourea addition resulted in the reductions of 77.6-99.8% and 36.4-98.1% in the yield of polychlorinated naphthalenes from naphthalene chlorination mediated by CuCl2 and FeCl3 at 150-300 °C, respectively. The inhibition efficiency of chlorination presented a decreasing tendency with increasing reaction temperature and O2 content in flue gas. X-ray diffraction analysis revealed that the thiourea-induced reduction of highly active Cu (II) and Fe (III) chlorides to less active Cu (I) and Fe (II) chlorides was a primary mechanism for inhibiting aromatic chlorination. [thiourea-Cu]+ complex generated during the reduction process could be transformed into CuS and Cu2S, and isomeric reaction product NH4SCN could react with Cu2+ to produce Cu(SCN)2 and then also form Cu sulfides, suggesting sulfidization of Cu chloride was another important inhibition mechanism. Chlorination inhibition induced by the volatile decomposition products of thiourea might only play a minor role.

Mechanistic Insights for Dimethyl Sulfoxide Catalyzed Aromatic Chlorination Reactions

AbstractRecently, the dimethyl sulfoxide O=SMe2 catalyzed aromatic chlorination reaction using N‐chlorosuccinimides (NsCl) under mild conditions has proven useful for bioactive compounds potentially containing various functional groups such as amide and hydroxyl. A novel catalytic mechanism is revealed by extensive DFT calculations using the anisole PhOMe as electron‐rich model substrate. The Cl+ transfer from NsCl to O=SMe2 slowly reacts via the S‐chloro sulfoxonium O=SClMe2+ to the S‐chloro ylide O=SClMeCH2, followed by facile Cl+ transfer from NsCl to the ylide CH2 site to initialize efficient electrophilic Cl+ transfer to nucleophilic substrates. According to the new proposal, the polarizable S and electronegative O sites of O=SMe2 may act as efficient Cl+ and H+ shuttles, respectively, in catalytic aromatic chlorination. If O=SMe2 is present in high concentration, it can trap intermediate SMe2OH+ into a stable H+‐bound dimer (SMe2O)2H+ to inhibit efficient protic NsCl activation. These mechanistic insights may be generally useful for the rational design of novel dual functional halonium transfer catalysts.

Ultrathin Fe–N –C single-atom catalysts with bifunctional active site for simultaneous production of ethylene and aromatic chlorides

Abstract Ethylene evolution reaction (EER) by electrochemical dechlorination of 1,2-dichloroethane is a promising and an economical strategy. The process is however severely impeded by the poor reactivity of catalysts, the accumulation of HCl in the electrolyte as well as low value-added by-products at anode. Herein, a bifunctional ultrathin Fe–Nx–C single-atom catalysts (SACs) has been successfully prepared and investigated as both cathode and anode material for EER and aromatic chlorination reaction (ACR), respectively. The generated HCl was recycled as a chlorinating reagent. The Fe–Nx–C SACs exhibited an excellent electrocatalytic performance simultaneously for both EER and ACR with high ethylene and para–chloroanisole selectivity obtained. The first-principles calculations indicated that Fe–N4 was the dominating catalytic active site for the generation of ethylene as well as para–chloroanisole. The coupling strategy of ACR at anode not only can accelerate the reaction rate of EER, but also provide a highly-efficient and atom-economical approach for the production of valuable ethylene and aromatic chlorides.

High performance polyester reverse osmosis desalination membrane with chlorine resistance

Chlorination is a common practice to prevent biofouling in municipal water supplies, wastewater reuse and seawater desalination. However, polyamide thin-film composite reverse osmosis membranes—the premier technology for desalination and clean-water production—structurally deteriorate when continually exposed to chlorine species. Here, we use layer-by-layer interfacial polymerization of 3,5-dihydroxybenzoic acid with trimesoyl chloride to fabricate a polyester thin-film composite reverse osmosis membrane that is chlorine-resistant in neutral and acidic conditions. Strong steric hindrance and an electron-withdrawing group effectively prevent direct aromatic chlorination, and residual OH groups capped with isophthaloyl dichloride preclude reaction with active chlorine. The poly(isophthalester) membrane exhibits high salt rejection (99.1 ± 0.2%) and water permeability (2.97 ± 0.13 l m−2 h−1 bar−1), even after demonstrating biofouling prevention with chlorine (50 mg l−1 of NaOCl for 15 min). We anticipate that our chlorine-resistant membrane will greatly advance reverse osmosis desalination as a sustainable technology to meet the global challenge of water supply. Reverse osmosis membranes are the primary technology used for desalination and wastewater recycling, but they are prone to biofouling and subsequent performance deterioration due to poor tolerance to disinfecting agents such as chlorine. Here a chlorine-resistant polyester reverse osmosis membrane is developed to prevent biofouling and increase the sustainability of desalination and wastewater reuse.

Use of α-cyclodextrin to Promote Clean and Environmentally Friendly Disinfection of Phenolic Substrates via Chlorine Dioxide Treatment.

The use of chlorine dioxide to disinfect drinking water and ameliorate toxic components of wastewater has significant advantages in terms of providing safe water. Nonetheless, significant drawbacks toward such usage remain. These drawbacks include the fact that toxic byproducts of the disinfection agents are often formed, and the complete removal of such agents can be challenging. Reported herein is one approach to solving this problem: the use of α-cyclodextrin to affect the product distribution in chlorine dioxide-mediated decomposition of organic pollutants. The presence of α-cyclodextrin leads to markedly more oxidation and less aromatic chlorination, in a manner that is highly dependent on analyte structure and other reaction conditions. Mechanistic hypotheses are advanced to explain the cyclodextrin effect, and the potential for use of α-cyclodextrin for practical wastewater treatment is also discussed.

Tungstate-Catalyzed Biomimetic Oxidative Halogenation of (Hetero)Arene under Mild Condition.

SummaryAryl halide (Br, Cl, I) is among the most important compounds in pharmaceutical industry, material science, and agrochemistry, broadly utilized in diverse transformations. Tremendous approaches have been established to prepare this scaffold; however, many of them suffer from atom economy, harsh condition, inability to be scaled up, or cost-unfriendly reagents and catalysts. Inspired by vanadium haloperoxidases herein we presented a biomimetic approach for halogenation (Br, Cl, I) of (hetero)arene catalyzed by tungstate under mild pH in a cost-efficient and environment- and operation-friendly manner. Broad substrates, diverse functional group tolerance, and good chemo- and regioselectivities were observed, even in late-stage halogenation of complex molecules. Moreover, this approach can be scaled up to over 100 g without time-consuming and costly column purification. Several drugs and key precursors for drugs bearing aryl halides (Br, Cl, I) have been conveniently prepared based on our approach.

U.S. Food and Drug Administration-Certified Food Dyes as Organocatalysts in the Visible Light-Promoted Chlorination of Aromatics and Heteroaromatics.

Seven FDA-certified food dyes have been investigated as organocatalysts. As a result, Fast Green FCF and Brilliant Blue FCF have been discovered as catalysts for the chlorination of a wide range of arenes and heteroarenes in moderate to excellent yields and high regioselectivity. Mechanistic investigations of the separate systems indicate that different modes of activation are in operation, with Fast Green FCF being a light-promoted photoredox catalyst that is facilitating a one-electron oxidation of N-chlorosuccinimide (NCS) and Brilliant Blue FCF serving as a chlorine-transfer catalyst in its sulfonphthalein form with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) as stoichiometric chlorine source. Dearomatization of naphthol and indole substrates was observed in some examples using the Brilliant Blue/DCDMH system.

DMSO-catalysed late-stage chlorination of (hetero)arenes

The chlorination of a bioactive compound can change its physiological properties and improve its pharmacokinetic and pharmacological profiles. It therefore has been an important strategy for drug discovery and development. However, the direct aromatic chlorination of complex bioactive molecules is too difficult to be practical. In fact, many functional groups such as hydroxyls, amines, amides or carboxylic acids may strongly restrain the reactivity of Cl+ by forming a halogen bond. Here we report a highly efficient aromatic chlorination of arenes that is catalysed by dimethyl sulfoxide with N-chlorosuccinimide as the chloro source. The mild conditions, easy-availability and stability of the catalyst and reagents, as well as good functional-group tolerance, showed the approach to be a versatile protocol for the late-stage aromatic chlorination of complex natural products, drugs and peptides. The multi-gram experiment and low-cost of N-chlorosuccinimide and dimethyl sulfoxide shows great potential for drug discovery and development in industrial applications. Late-stage aromatic chlorination of active pharmaceutical ingredients has enormous potential in drug discovery yet still features limited applicability due to issues of functional-group tolerance. Now, dimethyl sulfoxide is reported as catalyst for the chlorination of a diverse family of bioactive molecules in combination with N-chlorosuccinimide.

Starch hydrolysis using maltogenase immobilized via different techniques

A series of modified poly(urethane-urea) carriers for immobilization of maltogenase from Bacillus stearothermophilus were presented. Poly(urethane-urea) microparticles (PUU) from poly(vinyl alcohol) and isophorone diisocyanate were modified with ethylenediamine, glutaraldehyde, trichlorotriazine and gold nanoparticles (AuNPs). Covalent attachment of enzyme to carrier via active isocyanate, aldehyde or aromatic chlorine group or electrostatic adsorption to AuNPs was performed. Maximal surface area (218.3 m2/g) was estimated for PUU microparticles modified with ethylenediamine and decorated with AuNPs. The high efficiency and yield of enzyme immobilization onto PUU-EDA/AuNPs were determined. Properties of maltogenase immobilized onto PUU carriers were compared to crosslinked enzyme aggregates from maltogenase (CLEA-maltogenase). The determined values of KM were 21.29 mM, 22.46 mM and 61.72 mM for soluble, CLEA-maltogenase and immobilized onto PUU-EDA/AuNPs, respectively. Hydrolysis of wheat starch catalyzed by immobilized maltogenase in continuous mini-reactor was more effective in comparison to CLEA-maltogenase; obtained dextrose equivalent was 28.9% and amount of maltose was 26.6%.

Phosphonium‐Based Ionic Liquids Used as Reagents or Catalysts

AbstractThe role and enlarged importance of ionic liquids (ILs) in chemical reactions were already exhaustively demonstrated. The aim of this review is to promote the family of the phosphonium‐based ILs used as reagents and catalysts, which gained increased interest in the last decade. The common and beneficial properties of ILs refer to their negligible vapour pressure, non‐toxicity, reusability, and high thermal stability. Therefore, phosphonium‐based ionic liquids are used successfully as catalysts and reagents in many chemical reactions, and additionally allow the syntheses in mild reaction conditions. Phosphonium ILs have proved their catalytic efficiency in many reactions such as epoxidation of olefins and allylic alcohol, in synthesis of alpha‐aminophosphonates, beta‐ketophosphonates, nitrogen‐containing bisphosphonates, the Michaelis‐Arbuzov reactions, esterification, coupling reaction, aromatic chlorination, dehydrogenation. The major advantage of phosphonium‐based ILs used as catalysts is that they can be reused with only little loss of catalytic activity. Phosphonium ILs revealed their potential as Wittig reagents, halogenation reagents for bromination and bromo‐chlorination reactions with alkenes and alkynes, as monomer and as initiator in frontal polymerization of acrylates. From the literature data, it can be concluded that due to their structure and physical‐chemical properties phosphonium ILs can be tailored function of their purpose.

Effects of the Hydrogen Bonding Network on Electrophilic Activation and Electrode Passivation: Electrochemical Chlorination and Bromination of Aromatics

AbstractWe have developed an environmentally friendly electrocatalytic protocol for the chlorination and bromination of electron‐rich arenes and aromatic boronic acids. The hydrogen bonding network generated from hexafluoroisopropanol (HFIP) and AcOH plays a vital role in the activation of halogen electrophiles generated electrochemically. The hydrogen bonding network also plays an essential role in the reduction of electrode passivation.

Efficient Electrocatalysis for the Preparation of (Hetero)aryl Chlorides and Vinyl Chloride with 1,2-Dichloroethane.

Although the application of 1,2-dichloroethane (DCE) as a chlorinating reagent in organic synthesis with the concomitant release of vinyl chloride as a useful byproduct is a fantastic idea, it still presents a tremendous challenge and has not yet been achieved because of the harsh dehydrochlorination conditions and the sluggish C-H chlorination process. Here we report a bifunctional electrocatalysis strategy for the catalytic dehydrochlorination of DCE at the cathode simultaneously with anodic oxidative aromatic chlorination using the released HCl as the chloride source for the efficient synthesis of value-added (hetero)aryl chlorides. The mildness and practicality of the protocol was further demonstrated by the efficient late-stage chlorination of bioactive molecules.