Electrophilic Aromatic Substitution Research Articles

How Do Face-to-Face Stacked Aromatic Rings Activate Each Other to Electrophilic Aromatic Substitution?

We have found that face-to-face π-stacked aromatic rings show the propensity to activate one another toward electrophilic aromatic substitution through direct influence of the probe aromatic ring by the adjacent stacked ring, rather than through the formation of relay or "sandwich complexes." This activation remains in force even when one of the rings is deactivated through nitration. The resulting dinitrated products are shown to crystallize in an extended parallel offset stacked form, in stark contrast to the substrate.

Electrophilic substitution reactions of thiophene and thieno[2,3-b]thiophene heterocycles: a DFT study

Abstract We determined the most preferred site for the electrophilic aromatic substitution (SEAr) reactions of thiophene 1 and thieno[2,3-b]thiophene 2 using the N-chlorosuccinimide electrophile in the gas phase and in acetic acid. The B3LYP/6-311G(d), B3LYP-D3/6-311G(d) and M06-2X/6-311G(d) methods were employed to investigate the SEAr reaction mechanisms. We found that, compared to the β-carbon atom, the α-carbon atom in both 1 and 2 is preferred for electrophilic attack both kinetically and thermodynamically.

The reaction pathway and mechanism of 2,4-dichlorophenol removal by modified fly ash-loaded nZVI/Ni particles.

Nanoscale zero-valent iron (nZVI) is more valuable in environmental restoration than other materials. Chemical treatment of fly ash (CFA) was employed as a support material to disperse iron nickel bimetal nanoparticles (CFA-nZVI/Ni) to remove 2,4-dichlorophenol (2,4-DCP). Batch experiments showed that 2,4-DCP was completely removed by CFA-nZVI/Ni, and an optimal loading ratio was 8:1. The degradation of 2,4-DCP by CFA-nZVI/Ni was a chemical control reaction with an activation energy of 95.6 kJ mol-1 and followed pseudo-first-order kinetics. The addition of Cl- increased the removal rate of 2,4-DCP by 4%, while the addition of CO32- and SO42- decreased the removal rate of 2,4-DCP by 32% and 72.3%, respectively. The removal process of 2,4-DCP by CFA-nZVI/Ni included adsorption and reduction. The 2-CP (7.1 mg/L) and 4-CP (11.6 mg/L) could be converted to phenol using the CFA-nZVI/Ni system. Cl on the para-position of 2,4-DCP was simpler to remove than on the ortho-position. The following steps were taken in the electrophilic substitution reaction between substituted phenols and hydrogen radicals: 2,4-DCP > 2-CP > 4-CP > phenol. This research provides a novel concept to effectively remove 2,4-DCP and mechanism analysis.

Chlorination of amides: Kinetics and mechanisms of formation of N-chloramides and their reactions with phenolic compounds

Amides are common constituents in natural organic matter and synthetic chemicals. In this study, we investigated kinetics and mechanisms of the reactions of chlorine with seven amides, including acetamide, N-methylformamide, N-methylacetamide, benzamide, N-methylbenzamide, N-propylbenzamide, and N-(benzoylglycyl)glycine amide. Apparent second-order rate constants for the reactions of the amides with chlorine at pH 8 are in the range of 5.8 × 10−3 – 1.8 M−1s−1 and activation energies in the range of 62-88 kJ/mol. The second-order rate constants for the reactions of chlorine with different amides decrease with increasing electron donor character of the substituents on the amide-N and N-carbonyl-C in the amide structures. Hypochlorite (‒OCl) dominates the reactions of chlorine with amides yielding N-chloramides with species-specific second-order rate constants in the range of 7.3 × 10−3 – 2.3 M−1s−1. Kinetic model simulations suggest that N-chlorinated primary amides further react with HOCl with second-order rate constants in the order of 10 M−1s−1. The chlorination products of amides, N-chloramides are reactive towards phenolic compounds, forming chlorinated phenols via electrophilic aromatic substitution (phenol and resorcinol) and quinone via electron transfer (hydroquinone). Meanwhile, N-chloramides were recycled to the parent amides. At neutral pH, apparent second-order rate constants for the reactions between phenols and N-chloramides are in the order of 10−4-0.1 M−1s−1, comparable to those with chloramine. The findings of this study improve the understanding of the fate of amides and chlorine during chlorination processes.

Skeletal Transformation of Unactivated Arenes Enabled by a Low-Temperature Dearomative (3 + 2) Cycloaddition.

Simple aromatic compounds like benzene are abundant feedstocks, for which the preparation of derivatives chiefly begins with electrophilic substitution reactions or, less frequently, reductions. Their high stability makes them particularly reluctant to participate in cycloadditions under ordinary reaction conditions. Here, we demonstrate the exceptional ability of 1,3-diaza-2-azoniaallene cations to undergo formal (3 + 2) cycloadditions with unactivated benzene derivatives below room temperature, providing thermally stable dearomatized adducts on a multi-gram scale. The cycloaddition, which tolerates polar functional groups, activates the ring toward further elaboration. On treatment with dienophiles, the cycloadducts undergo a (4 + 2) cycloaddition-cycloreversion cascade to yield substituted or fused arenes, including naphthalene derivatives. The overall sequence results in the transmutation of arenes through an exchange of the ring carbons: a two-carbon fragment from the original aromatic ring is replaced with another from the incoming dienophile, introducing an unconventional disconnection for the synthesis of ubiquitous aromatic building blocks. Applications of this two-step sequence to the preparation of substituted acenes, isotopically labeled molecules, and medicinally relevant compounds are demonstrated.

Fractional condensation and aging of pyrolysis oil from cotton stalk

The current study is to investigate a multi-condenser system for separating pyrolytic vapors as a promoting method to produce bio-oils that are more impervious to aging. Bio-oil vapors produced by fast pyrolysis of cotton stalk in a fluidized bed reactor at a temperature of 500 °C and were divided by a fractional condensation system into four fractions. The results showed that the stability of the fractional bio-oil was improved because most of the reactive aliphatic compounds with small molecules involving water rich organic acids, aldehydes and ketones were effectively separated from the other components. It was found out that the stability of bio-oil was affected by the active chemicals derived from fast pyrolysis as well as the aqueous acidic condition of bio-oils because most polymerization, condensation and electrophilic addition substitution reactions need the presence of H+ to be the catalyst. The observation pointed out that the suspended solid particles (SS) in bio-oils can be suppressed by separating conventional bio-oils into different stages by means of concentrating the initial SS in a certain fraction.

Regiodivergent C-H Acylation of Arenes by Switching from Ionic to Radical Type Chemistry Using NHC-Catalysis.

The Friedel-Crafts acylation which belongs to the class of electrophilic aromatic substitutions is a highly valuable and versatile reaction in synthesis. Regioselectivity is well predictable and determined by electronic as well as steric factors of the (hetero)arene substrate. In this communication, a radical approach for the acylation of arenes and heteroarenes is presented. C-H Acylation is achieved through mild cooperative photoredox/NHC radical catalysis with the cross coupling of an arene radical cation with an NHC-bound ketyl radical as a key step. As compared to the classical Friedel-Crafts acylation, a regiodivergent outcome is observed upon switching from the ionic to the radical mode. In these divergent reactions, aroyl fluorides act as the acylation reagents in both the ionic as well as the radical process.

Regiodivergente C−H‐Acylierung von Aromaten durch Wechsel von ionischer zu radikalischer Chemie unter Verwendung von NHC‐Katalyse

AbstractDie Friedel–Crafts‐Acylierung, die zur Klasse der elektrophilen aromatischen Substitutionen gehört, ist eine äußerst wertvolle und vielseitige Reaktion in der Synthese. Die Regioselektivität ist gut vorhersagbar und wird sowohl durch elektronische als auch durch sterische Faktoren des verwendeten (Hetero)Aromaten bestimmt. In dieser Mitteilung wird ein radikalischer Ansatz für die Acylierung von Aromaten und Heteroaromaten vorgestellt. Die C−H‐Acylierung erfolgt durch milde kooperative Photoredox/NHC‐Radikal‐Katalyse mit der Kreuzkupplung eines Arenradikalkations mit einem NHC‐gebundenen Ketylradikal als Schlüsselschritt. Im Vergleich zur klassischen Friedel–Crafts‐Acylierung wird beim Wechsel vom ionischen zum radikalischen Modus ein regiodivergentes Ergebnis beobachtet. Bei diesen divergenten Reaktionen fungieren Aroylfluoride als Acylierungsreagenzien sowohl im ionischen als auch im radikalischen Prozess.

Formal [2+1] Cycloadditions of a Metallacyclopentadiene Unit with Alkynes: Constructing Tetracyclic Conjugated Frameworks with Bridgehead Metals

Comprehensive SummaryMetallacyclopentadienes play a vital role in transition‐metal mediated and catalyzed cycloaddition reactions of alkynes. Though versatile reactions of metallacyclopentadienes with alkynes have been disclosed, [2+1] cycloadditions of metallacyclopentadienes and alkynes have never been discovered. In present work, we report the formal [2+1] cycloadditions of a metallacyclopentadiene unit with a broad scope of commercial alkynes, providing a facile strategy to construct tetracyclic conjugated compounds. The deuterated experiment indicates a metal vinylidene intermediate has been involved in [2+1] cycloaddition. Moreover, the electrophilic substitution reaction of the tetracyclic conjugated compound with the aid of density functional theory (DFT) calculated Fukui functions is investigated. These tetracyclic conjugated compounds exhibit broad absorption spectra in the whole visible region which could be employed as potential photovoltaic materials.

Synthesis of Rhodomyrtone Analogs Modified at C7

AbstractWe developed a route to rhodomyrtone analogs that feature different acyl groups at C7. Since electrophilic substitution reactions on the aryl part of the rhodomyrtone core led to C5 derivatives, the C5 position was blocked by a chlorine. Subsequent Duff type formylation followed by Grignard addition to the aldehyde group and oxidation gave various phenones. The benzyl protecting groups were removed by hydrogenation or boron tribromide. Some derivatives turned out to be quite active against multiple resistant Staphylococcus aureus strains and a rhodomyrtone resistant mutant (RomR). The chlorine at C5 seems to have a beneficial effect on the antibacterial activity.

Dual Photochemical H-Atom Transfer & Cobalt Catalysis for the Desaturative Synthesis of Phenols from Cyclohexanones.

Phenols are integral aromatic molecules widely encountered in the structure of natural products and routinely utilised for the synthesis of high-value materials. Accessing highly substituted derivatives can often be difficult especially when their functionalization pattern does not match the intrinsic reactivity leveraged by electrophilic aromatic substitution (SEAr) chemistry. Here we provide an alternative and mechanistically distinct approach for phenol synthesis using saturated cyclohexanone precursors. This process operates at ambient temperature, under simple purple light irradiation, and features a dual catalytic manifold carrying four sequential H-atom transfer processes.

Dualkatalytisch‐Photochemische H‐Atomtransfer/Kobaltkatalysesequenz Ermöglicht Desaturative Synthese von Phenolen aus Cyclohexanonen

AbstractPhenole gehören zu den grundlegendsten aromatischen Strukturen, die nicht nur in einer Vielzahl von Naturstoffen zu finden sind, sondern auch routinemäßig für die Herstellung von wertvollen Produkten eingesetzt werden. Die Synthese hochsubstituierter Phenolderivate kann jedoch äußerst komplex sein, wenn das gewünschte Substitutionsmuster nicht durch die dirigierenden Effekte der elektrophilen aromatischen Substitution (SEAr) erreicht werden kann. In diesem Aufsatz präsentieren wir einen alternativen und mechanistisch einzigarten Ansatz zur Phenolsynthese, der saturierte Cyclohexanone als Ausgangsstoffe verwendet. Dieser bei Raumtemperatur ablaufende Prozess wird durch die Nutzung von violettem Licht ermöglicht und kennzeichnet sich durch den Einsatz einer Anthrachinon‐Kobalt‐Dualkatalyse, welcher vier aufeinanderfolgende Wasserstoffatomtransfers ermöglicht.

Enantioselective Sequential Catalytic Arylation-Fukuyama Cross-coupling of 1,1-Biszincioalkane Linchpins.

1,1-Bis(iodozincio)alkanes are used as dinucleophilic linchpins in an enantioselective double cross-coupling reaction sequence involving aryl iodides and then thioesters. The two catalytic C-C bond-forming reactions are achieved in the same pot through two distinct palladium-based catalytic systems: a first non-enantioselective one delivering configurationally labile secondary benzylzinc species from an achiral precursor, and a second enantioconvergent one that operates a highly efficient dynamic kinetic resolution of the racemic intermediates. This strategy, new in the area of asymmetric synthesis through two consecutive electrophilic substitution reactions of geminated C(sp3 )-organodimetallics, provides useful methodology to access in a modular fashion acyclic α-disubstituted ketone products with very high enantiomeric purity.

Preparation and evaluation of radiolabeled gliclazide parenteral nanoemulsion as a new tracer for pancreatic β-cells mass

Purpose The present investigation aims to develop and evaluate a radiopharmaceutical for targeting and assessing β-cells mass based on gliclazide, an antidiabetic drug that specifically binds the sulfonylurea receptor unique to the β-cells of the pancreas. Methods Conditions were optimized to radiolabel gliclazide with radioiodine via electrophilic substitution reaction. Then, it was formulated as a nanoemulsion system using olive oil and egg lecithin by hot homogenization followed by ultrasonication. The system was assessed for its suitability for parenteral administration and drug release. Then, the tracer was evaluated in silico and in vivo in normal and diabetic rats. Results and conclusions The labeled compound was obtained with a high radiochemical yield (99.3 ± 1.1%) and good stability (>48 h). The radiolabeled nanoemulsion showed an average droplet size of 24.7 nm, a polydispersity index of 0.21, a zeta potential of −45.3 mV, pH 7.4, an osmolality of 285.3 mOsm/kg, and viscosity of 1.24 mPa.s, indicating suitability for parenteral administration. In silico assessment suggested that the labeling did not affect the biological activity of gliclazide. The suggestion was further supported by the in vivo blocking study. Following intravenous administration of nanoemulsion, the pancreas uptake was highest in normal rats (19.57 ± 1.16 and 12 ± 0.13% ID) compared to diabetic rats (8.51 ± 0.16 and 5 ± 0.13% ID) at 1 and 4 h post-injection, respectively. All results supported the feasibility of radioiodinated gliclazide nanoemulsion as a tracer for pancreatic β-cells.

Evidence of a Wheland Intermediate in Carboxylate-Assisted C(sp2)−H Activation by Pd(IV) Active Catalyst Species Studied via DFT Calculations

Evidence of a Wheland intermediate in carboxylate-assisted C−H activation was found using DFT calculations when the Pd(IV) catalyst species was postulated as the active catalyst species (ACS). In order to delineate the reaction mechanism of Pd-catalyzed bisarylation of 3-alkylbenzofuran, five hypothetical catalyst species, [Pd(OAc)(PMe3)(Ph)] (I), [Pd(OAc)2] (II), [Pd(OAc)2(PMe3)] (III), [Pd(OAc)2(Ph)]+ (IV) and [Pd(OAc)2(PMe3)(Ph)]+ (V) were tested as potential ACS candidates. The catalyst species I, previously reported as an ACS in the context of ambiphilic metal−ligand assistance or a concerted metalation-deprotonation mechanism, was unsuccessful, with maximum activation barriers (ΔG‡max) for the C(sp2)−H and C(sp3)−H activations of 33.3 and 51.4 kcal/mol, respectively. The ΔG‡max values for the C(sp2)−H and C(sp3)−H activations of II−V were 23.8/28.7, 32.0/49.6, 10.9/10.9, and 36.0/36.0 kcal/mol, respectively, indicating that ACS is likely IV. This catalyst species forms an intermediate state (IV_1) before proceeding to the transition state (IV_TS1,2) for C(sp2)−H activation, in which C(2) atom of 3-methylbenzofuran has a substantial σ-character. The degree of σ-character of the IV_1 state was further evaluated quantitatively in terms of geometric parameters, partial charge distribution, and activation strain analysis. The analysis results support the existence of a Wheland intermediate, which has long been recognized as the manifestation of the electrophilic aromatic substitution mechanism yet never been identified computationally.

4,4′-Dicyano- versus 4,4′-Difluoro-BODIPYs in Chemoselective Postfunctionalization Reactions: Synthetic Advantages and Applications

The presence of F or CN substituents at boron in BODIPYs causes a dramatic effect on their reactivity, which allows their chemoselective postfunctionalization. Thus, whereas 1,3,5,7-tetramethyl B(CN)2-BODIPYs displayed enhanced reactivity in Knoevenagel condensations with aldehydes, the corresponding BF2-BODIPYs can experience selective aromatic electrophilic substitution (SEAr) reactions in the presence of the former. These (selective) reactions have been employed in the preparation of BODIPY dimers and tetramers, with balanced fluorescence and singlet oxygen formation, and all-BODIPY trimers and heptamers, with potential application as light-harvesting systems.

Arene C–H borylation strategy enabled by a non-classical boron cluster-based electrophile

Introducing a tri-coordinate boron-based functional group (e.g., boronic ester) into an unactivated C–H bond in the absence of directing groups is an ongoing challenge in synthetic chemistry. Despite previous developments in transition metal-catalyzed and -free approaches, C–H borylation of sterically hindered arenes remains a largely unsolved problem to date. Here, we report a synthetic strategy of a two-step, precious metal-free electrophilic C–H borylation of sterically hindered alkyl- and haloarenes to generate aryl boronic esters. The first step relies on electrophilic aromatic substitution (EAS) induced by cage-opening of Cs2[closo-B10H10], forming a 6-Ar-nido-B10H13 product containing a B–C bond, followed by a cage deconstruction of arylated decaboranes promoted by diols. The combination of these two steps allows for the preparation of aryl boronic esters that are hardly accessible by current direct C–H borylation approaches. This reaction does not require any precious metals, highly-engineered ligands, pre-functionalized boron reagents, or inert conditions. In addition, the unique properties of a non-classical boron cluster electrophile intermediate, B10H13+, afford a regioselectivity with unique steric and electronic control without the undesirable side reactions.

B(9)-OH-o-Carboranes: Synthesis, Mechanism, and Property Exploration.

Herein, we present a chemically robust and efficient synthesis route for B(9)-OH-o-carboranes by the oxidation of o-carboranes with commercially available 68% HNO3 under the assistance of trifluoromethanesulfonic acid (HOTf) and hexafluoroisopropanol (HFIP). The reaction is highly efficient with a wide scope of carboranes, and the selectivity of B(9)/B(8) is up to 98:2. The success of this transformation relies on the strong electrophilicity and oxidizability of HNO3, promoted through hydrogen bonds of the Brønsted acid HOTf and the solvent HFIP. Mechanism studies reveal that the oxidation of o-carborane involves an initial electrophilic attack of HNO3 to the hydrogen atom at the most electronegative B(9) of o-carborane. In this transformation, the hydrogen atom of the B-H bond is the nucleophilic site, which is different from the electrophilic substitution reaction, where the boron atom is the nucleophilic site. Therefore, this is an oxidation-reduction reaction of o-carborane under mild conditions in which N(V) → N(III) and H(-I) → H(I). The derivatization of 9-OH-o-carborane was further examined, and the carboranyl group was successfully introduced to an amino acid, polyethylene glycol, biotin, deoxyuridine, and saccharide. Undoubtedly, this approach provides a selective way for the rapid incorporation of carborane moieties into small molecules for application in boron neutron capture therapy, which requires the targeted delivery of boron-rich groups.

Synthesis and Characterization of a Masked Terminal Nickel-Oxide Complex.

In exploring terminal nickel-oxo complexes, postulated to be the active oxidant in natural and non-natural oxidation reactions, we report the synthesis of the pseudo-trigonal bipyramidal NiII complexes (K)[NiII (LPh )(DMF)] (1[DMF]) and (NMe4 )2 [NiII (LPh )(OAc)] (1[OAc]) (LPh =2,2',2''-nitrilo-tris-(N-phenylacetamide); DMF=N,N-dimethylformamide; - OAc=acetate). Both complexes were characterized using NMR, FTIR, ESI-MS, and X-ray crystallography, showing the LPh ligand to bind in a tetradentate fashion, together with an ancillary donor. The reaction of 1[OAc] with peroxyphenyl acetic acid (PPAA) resulted in the formation of [(LPh )NiIII -O-H⋅⋅⋅OAc]2- , 2, that displays many of the characteristics of a terminal Ni=O species. 2 was characterized by UV-Vis, EPR, and XAS spectroscopies and ESI-MS. 2 decayed to yield a NiII -phenolate complex 3 (through aromatic electrophilic substitution) that was characterized by NMR, FTIR, ESI-MS, and X-ray crystallography. 2 was capable of hydroxylation of hydrocarbons and epoxidation of olefins, as well as oxygen atom transfer oxidation of phosphines at exceptional rates. While the oxo-wall remains standing, this complex represents an excellent example of a masked metal-oxide that displays all of the properties expected of the ever elusive terminal M=O beyond the oxo-wall.

Development of Novel Methodologies for Functionalization of Isoxazoles

Isoxazole is a five-membered heteroaromatic ring that is a highly important framework with widespread applications in pharmaceuticals and agrochemicals. Indeed, the isoxazole ring has desirable pharmacological activity because its two contiguous electronegative heteroatoms (nitrogen and oxygen atoms) contribute to hydrogen bonding with various target enzymes and receptors inaccessible by other ring systems. This unique and significant utility has led to great interest in the synthesis of functionalized isoxazoles, and various synthetic approaches have been developed for this class of compounds. Current synthetic approaches are classified into following four groups: (a) 1,3-dipolar cycloaddition, (b) condensation, (c) cycloisomerization, and (d) direct functionalization. Despite the recent much effort on synthetic researches, however, direct functionalization of isoxazoles (approach d) has still been immature to produce a variety of multifunctionalized isoxazoles. We herein describe our recent studies on direct functionalization of isoxazoles based on the generation of 4-isoxazolyl anion species and the subsequent gold (I)-catalyzed electrophilic aromatic substitution type reactions and rhodium (III)-catalyzed carboxylate-directed C-H activation. These developed functionalization methodologies enabled access to novel isoxazole derivatives that are not readily synthesized by other means. In addition, our interest in photolysis of isoxazoles led us to find photochemical conversion of isoxazoles into 5-hydroxyimidazolines.