Mechanism Of Electrophilic Substitution Research Articles

Oxone® Mediated Regioselective C(sp2)−H Selenylation and Thiocyanation of Pyrazolo[1,5‐a]pyrimidines at Room Temperature

AbstractA mild Oxone® mediated reaction for direct regioselective C−H selenylation and thiocyanation of pyrazolo[1,5‐a]pyrimidines is established at ambient temperature. This practical and efficient methodology employs Oxone® as a user friendly, green, non‐toxic and cheap reagent to facilitate selenylation and thiocyanation at room temperature. The present method offers high regioselectivity, broad substrate scope, mild conditions and excellent yields. Further, this eco‐friendly approach could easily be extended for mild C−H selenylation and thiocyanation of other heterocycles. Mechanistic studies indicate that the reaction occurs through electrophilic substitution mechanism via generation of an electrophilic chalcogen species.

Regioselective C(sp2)-H halogenation of pyrazolo[1,5-a]pyrimidines facilitated by hypervalent iodine(iii) under aqueous and ambient conditions.

An efficient and mild approach has been developed for the regio-selective direct C3 halogenation of pyrazolo[1,5-a]pyrimidines employing readily available potassium halide salts and a hypervalent iodine(iii) reagent at ambient temperature. The protocol is both practical and environmentally friendly, utilizing water as a green solvent, potassium halides as an inexpensive and bench stable halogen source and PIDA as a non-toxic reagent, enabling clean and efficient halogenation at room temperature. The procedure yields a range of C3 halogenated pyrazolo[1,5-a]pyrimidines in good to excellent yields. Mechanistic studies suggest the involvement of electrophilic substitution mechanism in the halogenation process.

Activation of peroxymonosulfate via peroxyborate: Electrophilic substitution induced strong electrophile generation process

Although sulfate radical (SO4•−) based advanced oxidation processes (AOPs) is promising for the removal of stubborn organic contaminations, low utilization efficiency of peroxymonosulfate (PMS) has practically troubled the potential application of this water treatment technology. In this study, a novel strategy for ultrafast PMS decomposition was proposed using solid peroxyborate (PBO) as the catalyst. Over 80 % of PMS can be rapidly activated within 1 min. strong electrophilic H2O2BO2 rather than commonly recognized species was considered as the reactive species causing BPA degradation. Through thermodynamic DFT calculation, the catalytic mechanism was thoroughly clarified as the electrophilic substitution reaction between protonated perboric acid (H4BO4+) and ionized PMS (SO52-). Universality experiments showed that PMS/PBO system was a promising, efficient, and eco-friendly process for the degradation of selective contaminants. This work sheds novel lights on the mechanism of electrophilic substitution induced PMS activation, and provides a new idea for environmental remediation.

Reactivity of nitrogen species with inorganic and organic compounds in water.

Many studies on the reactive nitrogen species (RNS, ●NO2, ●NO and ●NH2) with pollutants in water have been performed to understand the abatement of inorganic and organic compounds by these species, and the mechanisms of the formation of oxidative transformation products, especially nitrogenous oxidized byproducts. In this review, approaches to generate RNS in aqueous solution is first presented, followed by a summary of their reactivity with a wide range of compounds. The second-order rate constants (k, M-1 s-1) for the reactivity of ●NO2 and ●NO with a wide range of inorganic radical and nonradical species were correlated with thermodynamic one-electron oxidation potentials (E0). The positive correlation between log(k) versus E0 suggests one-electron transfer reactions. The Hammett-type correlations were developed for the reactions of ●NO2 and ●NH2 with organic compounds, using the unsubstituted benzene as a reference molecule (i.e., Σσo,p,m=0) to calculate Σσo,p,m=σo+σp+σm for each organic molecule. Linear negative correlations of log(k) with Σσo,p,m were obtained for both ●NO2 and ●NH2, suggesting electrophilic substitution mechanism. The correlations presented herein may assist in eliminating organic micropollutants in water treatment and reuse processes.

Transformation of chlorobenzenes to chlorophenols by Mn(III) generated in permanganate/bisulfite process via an electrophilic substitution mechanism

Chlorobenzenes are a group of toxic compounds that have been widely used as intermediates in chemical synthesis, process solvents, pesticides, and hygiene products. In this study, we reported rapid transformation of chlorobenzenes by soluble Mn(III) generated in permanganate/bisulfite (PM/BS) process, which can be taken advantage of in practical treatment of chlorobenzenes. Chlorobenzenes with five or less chlorine atoms could be removed (10–83%) in PM/BS process within 5 s, while the fully chlorinated congener, hexachlorobenzene, could be hardly degraded. The removal efficiency of chlorobenzenes was not significantly impacted by changes in initial solution pH (4.0–8.0). Results of quenching experiments and UV–Vis spectra consistently indicated that Mn(III) was the primary reactive species responsible for the transformation of chlorobenzenes. Based on the degradation products detected for the chlorobenzene congeners, an electrophilic substitution mechanism was proposed, in which Mn(III) acted as a strong electrophile to attack the ortho/para positions on the benzene ring and subsequently transformed chlorobenzenes into more reactive chlorophenols. While most studies attributed the high reactivity of soluble Mn(III) towards organic contaminants to its strong oxidizing power, the findings of this study revealed that Mn(III) could act as a strong electrophilic reagent to initiate the degradation of chlorobenzenes. As PM was more efficient at mineralizing the phenolic products produced from degradation of chlorobenzenes compared to PM/BS and peroxymonosulfate, PM/BS coupled with PM process could be utilized as a fast and effective method for the treatment of chlorobenzenes.

Transition‐Metal‐Free Intermolecular Chlorodifluoromethylthiolation of Alkenes and Alkynes

AbstractA general and convenient method for the direct transition‐metal‐free intermolecular chlorodifluoromethylthiolation of a variety of unactivated alkenes and alkynes has been described. This methodology exhibits good functional group tolerance and is operationally simple. Mechanistic studies indicated an electrophilic substitution mechanism, and the strong electrophilic difluoromethylthiolating reagent HCF2SCl was generated in situ under standard reaction conditions. The developed protocol fulfils the requirements of sustainable and green chemistry.

Upgrading of thiophenic compounds from fuels over a silver-modified MoO3 catalyst under ambient conditions

The demand for heterocyclic sulfur compounds is increasingly in fine chemical industry, where the thiophenic sulfur impurities in fuels can be a potential recyclable feedstock. In this work, the catalytic upgrading of thiophenic sulfur compounds over a silver-modified MoO3 catalyst under ambient conditions was reported. Br2 and H2O2/HBr were used to convert thiophenic compounds in alkane and alcohol solutions. The conversion of various thiophenic compounds (thiophene, benzothiophene and dibenzothiophene) to the corresponding bromides reached up to 81.6 ~ 99.8%. The bromination path undergoes electrophilic substitution mechanism, and the transformation of mono- to dibromides is identified as the rate-determining step. The introduction of MoAg2O4 phase on MoO3 is rationalized to boost the conversion of mono-bromothiophene, which results in the selectivity of 2,5-dibromothiophene increased from 10% to over 50%. The optimized silver loading was 10% due to its high thiophene conversion and selectivity of dibromides. Silver modification of MoO3 rods not only stabilized the textural property of catalysts but also improved its bromination activity compared to the bulk MoO3 indicated by SEM and FTIR characterization. Density functional theory (DFT) calculation suggested that the formation of 2-bromothiphene and 2,5-dibromothiophene were preferred on the MoO3(111) and MoAg2O4(111) sites, respectively. The catalytic upgrading approach paves the way for the efficient utilization of thiophenic sulfur impurities in fuels to their value-added under mild conditions.

On the protonation and deuteration of N,N‐disubstituted 2‐aminothiophenes, 2‐aminothiazoles, and some 3‐amino substituted analogues

AbstractIn contrast to their carbocyclic aniline analogues, N,N‐diarylsubtituted 2‐aminothiophenes are not protonated at their N‐atoms but at the 5‐position or, to a smaller extent, at the 3‐position of the thiophene nucleus giving rise to cationic species of the Wheland type. However, 5‐formyl and 5‐acetyl‐substituted 2‐(N,N‐diarylamino)thiophenes are protonated at the corresponding carbonyl moieties. This finding not only enables insight into the mechanism of electrophilic substitution of N,N‐disubstituted 2‐aminothiophenes but also allows to prepare deurated 2‐aminothiophenes by treatment their non‐deuterated parent compounds with CF3COOD.

Diphenyl Oxide Copolyarylenephthalides with Different Ratio of Phthalide and Diphthalide Groups

The interbicopolycondensation of 3,3'-bis(4-phenoxyphenyl)-3,3'-diphthalide and diphenyl oxide with intermonomer, 4,4'-bis(2-carboxybenzoyl)diphenyl oxide pseudoacid dichloride, proceeding by the Friedel–Crafts electrophilic substitution mechanism is used for the synthesis of a number of new diphenyl oxide copolyarylenephthalides with different ratios of phthalide and diphthalide groups in the polymer chain. It is shown that the ratio of diphthalide (meso and racemic) and common phthalide groups in the main chain significantly affects the morphological structure of the copolymers. A side “rephthalidation” reaction is found, which consists in the catalytic cleavage of the diphthalide group accompanied by the generation of two phthaloyl carbocations, which, along with the intermonomer, interact with diphenyl oxide, participating in the polymer-forming reaction.

Transformation of Bisphenol AF during Aqueous Chlorination: Kinetics, Mechanisms, and Influence of pH

In this study, the reaction kinetics and degradation mechanism of bisphenol AF (BPAF) with hypochlorous acid (HOCl) were investigated for the first time. Our results showed that BPAF could be effectively degraded by chlorine over a wide pH range from 5.3 to 11.7, with apparent second-order rate constants (kapp) of 1.0–175.5 M–1 s–1 at temperature 25 ± 1.8 °C. By kinetic modeling, kapp of un-ionized and ionized BPAF (i.e., BPAF, BPAF–, and BPAF2–) were calculated to be 2.9 ± 1.1, (9.0 ± 0.4) × 103, and (1.4 ± 0.2) × 104 M–1 s–1, respectively. Five chlorinated BPAF (Cl-BPAF) were identified by a gas chromatography–mass spectrometry method, and confirmed by authentic materials synthesized in laboratory. By comparing the concentration evolution of BPAF and Cl-BPAF under each designated pH level, we found that (1) higher pH favored the electrophilic substitution mechanism and lower pH favored the electron transfer mechanism. (2) the electron transfer mechanism of BPAF with free chlorine may be attributed to the redox reaction of HOCl. (3) Aqueous pH dominated the formation ratio of Cl2–BPAF isomers due to the pH-dependence of the dissociation forms of precursor 3-Cl1BPAF. Considering the structural similarity of bisphenol analogues, similar relationship between pH and degradation kinetics or mechanism could be applied for other bisphenol analogues during chlorination.

Electrophilic and Nucleophilic Aromatic Substitutions are Mechanistically Similar with Opposite Polarity.

Confrontation of the recently formulated general mechanism of nucleophilic substitution in electron-deficient arenes with the well-known mechanism of electrophilic substitution revealed that these fundamental processes are mechanistically identical but proceed according to opposite polarity-an Umpolung relation. In this viewpoint this apparently controversial concept is supported by discussion of a variety of experimental results.

Carbamates: A Directing Group for Selective C-H Amidation and Alkylation under Cp*Co(III) Catalysis.

The selective reactivity of carbamate and thiocarbamate toward alkylation and amidation is reported under stable, high-valent, cost-effective cobalt(III) catalysis. This method reveals the wide possibility of designing a different branch of synthetically challenging yet highly promising asymmetric catalysts based on BINOL and SPINOL scaffolds. Late-stage C-H functionalization of l-tyrosine and estrone was also achieved through this approach. The mechanistic study shows that a base-assisted internal electrophilic substitution mechanism is operative here.

H-bond catalytic mechanism of aromatic electrophilic substitution between phenol and formaldehyde

Phenolic resins are widely used as moulding plastics, coatings, industrial bondings and ablative materials. An essential reaction step for preparing phenolic resins is aromatic electrophilic substitution. However, the current understanding of this reaction mechanism is kind of too general, making them not able to explain some phenomena such as highly exothermic characteristic of the early reaction stage between phenol and aldehyde under acid catalysis, and how attacking species form when the reaction begins. We studied the detailed catalytic mechanism by quantum mechanics. A new hydrogen-bond (H-bond) catalytic mechanism is suggested. It reveals that the essence of the acid catalytic mechanism is electrophile activation through hydrogen-bonding, and the substrate-catalyst complex formed through an H-bond is the attacking species. Besides, the study discloses that oxalate anion takes part in the reaction through bonding with arenium ion. The thermodynamic and kinetic characters based on this mechanism are quite different from the current theories.

Hydroxyl Radical-Coupled Electron-Transfer Mechanism of Flavin-Dependent Hydroxylases.

Class A flavin-dependent hydroxylases (FdHs) catalyze the hydroxylation of organic compounds in a site- and stereoselective manner. In stark contrast, conventional synthetic routes require environmentally hazardous reagents and give modest yields. Thus, understanding the detailed mechanism of this class of enzymes is essential to their rational manipulation for applications in green chemistry and pharmaceutical production. Both electrophilic substitution and radical intermediate mechanisms have been proposed as interpretations of FdH hydroxylation rates and optical spectra. While radical mechanistic steps are often difficult to examine directly, modern quantum chemistry calculations combined with statistical mechanical approaches can yield detailed mechanistic models providing insights that can be used to differentiate reaction pathways. In the current work, we report quantum mechanical/molecular mechanical (QM/MM) calculations on the fungal TropB enzyme that shows an alternative reaction pathway in which hydroxylation through a hydroxyl radical-coupled electron-transfer mechanism is significantly favored over electrophilic substitution. Furthermore, QM/MM calculations on several modified flavins provide a more consistent interpretation of the experimental trends in the reaction rates seen experimentally for a related enzyme, para-hydroxybenzoate hydroxylase. These calculations should guide future enzyme and substrate design strategies and broaden the scope of biological spin chemistry.

An environmentally benign and efficient synthesis of 4‐Selanylpyrazoles catalyzed by haloid salts in water

An environmentally benign procedure is developed for the preparation of 4‐selanylpyrazoles from pyrazoles and diselenides. Using haloid salts as catalysts and H2O2 as oxidant, this catalytic protocol is convenient in water at room temperature under open‐air condition, and is suitable for a wide variety of starting materials and provides a series of 4‐selanylpyrazoles in good yields. A plausible catalytic electrophilic substitution mechanism is hypothesized.

Click. Coordinate. Catalyze. Using CuAAC Click Ligands in Small‐Molecule Model Chemistry of Tyrosinase

AbstractThree triazolylmethylpyridine ligands are synthesized using the copper‐catalyzed azide‐alkyne cycloaddition (CuAAC). The corresponding copper(I) complexes are investigated as catalysts for the oxygenation of several monophenols, in analogy to the enzyme tyrosinase. Importantly, they show a higher catalytic activity than previously investigated systems. This is ascribed to the lower charge donation of the electron‐poor triazole heterocycle, supporting the hydroxylation of phenolic substrates by an electrophilic substitution mechanism.

Quantum chemical studies of azoles 13. Specific solvation effect on the calculated energetic parameters of the electrophilic substitution mechanism in thiazole via elimination–addition schemes

Energetic characteristics of electrophilic substitution reactions (hydroxonium ion as a model electrophile) in thiazole via the elimination–addition schemes in a wide range of pH of the medium were revealed on the basis of the results of analysis of quantum chemical calculations performed using the DFT/B3LYP/6-31G(d) and DFT/B3LYP/6-31++G(d,p) methods taking into account specific solvation effects.

Boron(III)‐Catalyzed C2‐Selective C−H Borylation of Heteroarenes

A BF3 ⋅Et2 O-catalyzed C2-selective C-H borylation of indoles with bis(pinacolato)diboron was developed to afford indole-2-boronic acid pinacol esters. A variety of functional groups were tolerated, and other heteroarenes like pyrrole and benzo[b]thiophene were also suitable substrates. An electrophilic substitution mechanism was proposed based on the preliminary mechanistic studies. This novel transformation utilizes simple and cheap BF3 ⋅Et2 O as catalyst and exhibits unusual C2 regioselectivity, providing a significant non-transition-metal-catalyzed C-H borylation and an efficient method towards the synthesis of C2-functionalized heteroarenes.

Boron(III)‐Catalyzed C2‐Selective C−H Borylation of Heteroarenes

AbstractA BF3⋅Et2O‐catalyzed C2‐selective C−H borylation of indoles with bis(pinacolato)diboron was developed to afford indole‐2‐boronic acid pinacol esters. A variety of functional groups were tolerated, and other heteroarenes like pyrrole and benzo[b]thiophene were also suitable substrates. An electrophilic substitution mechanism was proposed based on the preliminary mechanistic studies. This novel transformation utilizes simple and cheap BF3⋅Et2O as catalyst and exhibits unusual C2 regioselectivity, providing a significant non‐transition‐metal‐catalyzed C−H borylation and an efficient method towards the synthesis of C2‐functionalized heteroarenes.

H–D exchange between quercetin and solvent in the presence of AuI chloride complexes with DMSO: quantum chemical modeling

The pathways of H–D exchange between quercetin and solvent taking into account the effects of the medium are considered using quantum chemical calculations and the mechanism of selective H–D exchange reaction at the C(2′) position observed only in the presence of Au complexes is identified. It is shown that only the exchange processes in the A-ring have suffi- ciently low activation barriers. In the acidic and alkaline media, these processes occur at lower energies as compared with the reaction in the neutral system, which qualitatively agrees with the published experimental data. It was shown that the AuI chloride complex with DMSO is able to react with the C–H bond at the C(2′) position by the mechanism of electrophilic substitution under mild conditions.