Substitution Pathway Research Articles

Copper(II)-Catalyzed Amination of Aryl Chlorides in Aqueous Ammonia.

Anilines are ubiquitous in bio-active compounds and their synthesis can be achieved via metal-catalyzed cross-coupling reactions involving aryl halides. We describe an unusual, yet simple, CuII-catalyzed system for the amination of aryl chlorides in pure aqueous ammonia with 2.5 mol % catalyst loading under non-inert conditions. Different from previous systems, the reaction proceeds even without an additional organic solvent. Copper(II) sulfate in combination with 4,7-dimethoxy-1,10-phenanthroline enabled the amination of several aryl chlorides containing electron-neutral, -donating and -withdrawing groups to the corresponding anilines with good to excellent yields. The upscaling potential of the procedure has been shown by the synthesis at 50 mmol scale. The reaction proceeds as one of the rare cases of a CuII-assisted coupling, in contrast to the typical CuI-CuIII intermediates postulated for most Ullmann-type coupling reactions. The copper(II) center allows for a nucleophilic substitution pathway, enabled by the deprotonation of coordinated ammonia.

Redox-Induced Aromatic Substitution: A Study on Guanidino-Functionalized Aromatics.

Aromatic substitution of redox-active aromatic compounds could be initiated by a preceding redox step. We report on the different reaction pathways of such redox-induced substitution (RIAS) reactions between a redox-active guanidino-functionalized aromatic molecule (GFA) and an amine or guanidine. Oxidation of the GFA leads to an umpolung of the guanidine from a nucleophile to an electrophile and thereby enables addition of the amine or guanidine. Several examples are given, demonstrating the use of redox substitution in synthetic chemistry, e.g. for the convenient synthesis of novel N-heteropolycyclic molecules and unsymmetrically-substituted aromatics.

Ru(II)‐Catalyzed Weak Chelation‐Assisted Regioselective C4−H Aminomethyl Alkenylation of Indole

A Ruthenium catalyzed C4‐ aminomethyl alkenylation of indoles using substituted propargylamine as an alkenylating agent and pivaloyl as a weak chelating group has been demonstrated. A variety of substituted indoles and propargylamines furnished the desired product in good yields. Control experiments indicate that the C−H cleavage step is reversible and suggest the possibility of a base‐assisted internal electrophilic substitution (BIES) pathway.

C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates

Regioselective C–H functionalization of pyridines remains a persistent challenge due to their inherent electronically deficient properties. In this report, we present a strategy for the selective pyridine C3-H thiolation, selenylation, and fluorination under mild conditions via classic N−2,4-dinitrophenyl Zincke imine intermediates. Radical inhibition and trapping experiments, as well as DFT theoretical calculations, indicated that the thiolation and selenylation proceeds through a radical addition-elimination pathway, whereas fluorination via a two-electron electrophilic substitution pathway. The pre-installed electron-deficient activating N-DNP group plays a crucial and positive role, with the additional benefit of recyclability. The practicability of this protocol was demonstrated in the gram-scale synthesis and the late-stage modification of pharmaceutically relevant pyridines.

Photodegradation of bisphenol A (BPA) in coastal aquaculture waters: Influencing factors, products, and pathways

Bisphenol A (BPA), an endocrine-disrupting contaminant, is ubiquitous in the environment due to its presence in plastics, wastewater, and agricultural runoff. This study investigated the photodegradation behavior of BPA in coastal aquaculture waters near Qingdao, China. Lower salinity promoted BPA photodegradation, while higher salinity has an inhibitory effect, suggesting slower degradation in seawater compared to ultrapure water. Triplet-excited dissolved organic matter (3DOM*) was identified as the primary mediator of BPA degradation, with additional contributions from hydroxyl radicals (•OH), singlet oxygen (1O2), and halogen radicals (HRS). Alepocephalidae aquaculture water exhibited the fastest degradation rate, likely due to its high DOM and nitrate/nitrite (NO3−/NO2−) content, which are sources of 3DOM* and •OH. A positive correlation existed between NO3−/NO2− concentration and the BPA degradation rate. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) analysis identified the primary BPA photodegradation products, formed mainly through oxidative degradation, hydroxyl substitution, nitration, and chlorination pathways. Elucidating these photodegradation mechanisms provides valuable insights into the environmental fate and potential ecological risks of BPA in aquaculture environments. This knowledge can inform strategies for marine environmental protection and the development of sustainable practices.

Pd‐Catalyzed [3+6+3+6] Macrocyclizations of Aryl α‐Diazo‐β‐Ketoesters

AbstractThanks to Pd(II)‐catalysis, an efficient synthesis of unsaturated macrocycles is achieved by [3+6+3+6] condensation of cyclic ethers with aryl α‐diazo‐β‐ketoesters. The presence of the electron‐rich aryl ester moieties forbids the use of dirhodium complexes as these diazo decomposition catalysts provoke unforeseen intermolecular Csp2−H insertion reactions that derail the targeted reactivity. However, with Pd(acac)2, using high concentration conditions (1 M), a variety of 18‐membered macrocycles (16 examples) is afforded with both aryl and alkyl diazo reagents. Catalyst selection for either electrophilic aromatic substitution (Rh) or ylide (Pd) pathways are explained by computational approaches.

Feasibility study of renewable e-methanol production: A substitution pathway from blue to green

Feasibility study of renewable e-methanol production: A substitution pathway from blue to green

Self-Assembled Lanthanide Supramolecular Helicates: Efficient Catalysts for Synthesis of Heterocyclic Scaffolds

Geometrically unsaturated binuclear double-stranded metallohelicates constructed with pyridyl hydrazine ligands and lanthanide metal ions via metal-templated self-assembly. The single-crystal X-ray analysis suggests the formation of helical assembly through its coordination with pyridyl, azomethine nitrogen’s and ketonic oxygen with metal ions. Lanthanide ions are known to possess multiple coordination sites, other labile sites are occupied with solvents and anions. The lanthanide helicates are exhaustively characterized and adopted as a catalyst to synthesize benzothiazole scaffolds starting from 2-fluoroaniline and phenyl isothiocyanate substrates via tandem thiourea intermediate/cyclization pathway. The mechanistic investigation suggests the reaction proceeds via the nucleophilic aromatic substitution pathway. The protocols are extended for the synthesis of drug molecules such as Riluzole and Dimazole.

Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

Crystal-Site Engineering of Novel Na3KMg7(PO4)6-x(BO3)x:Eu2+ Phosphors for Full-Spectrum Lighting.

The "cyan gap" is the bottleneck problem in violet-driven full-spectrum white-light-emitting diodes (wLEDs) in healthy lighting. Accordingly, we develop a novel broadband-blue-cyan emission Na3KMg7(PO4)6-x(BO3)x:Eu2+ (NKMPB:Eu2+) phosphor via crystal-site engineering. This phosphor is derived from the Na3KMg7(PO4)6:Eu2+ phosphor, which shows desired abundant cyan emissive components. A comparative study is conducted to reveal the microstructure-property relationship and the key influential factors to its spectrum distribution. It can be found that the introduced (BO3)3- units can manipulate the site-selective occupation of Eu2+ activators, asymmetrically broadening the emission spectrum in NKMPB:Eu2+. Considering detailed luminescence performance analysis and the density functional theory calculations, a new substitution pathway of Eu2+ is created by substituting (PO4)3- with (BO3)3- units, making partial Eu2+ ions enter the Mg2+ (CN = 5, CN = 6) crystallographic sites, and yielding an extra emission band at 600 nm (16667 cm-1) and especially 501 nm (19960 cm-1). Meanwhile, a high-color-quality full-spectrum-emitting wLEDs was fabricated, upon 100 mA forward-bias current driven. Due to the achieved extra cyan emissive components of NKMPB:Eu2+, the constructed NKMPB:Eu2+-based wLEDs show better color rendering ability (∼90.9) than that of Na3KMg7(PO4)6:Eu2+-based wLEDs (∼86.3), and also demonstrate its great potential in full-spectrum healthy lighting.

Mechanistic Insights into the Proton Transfer and Substitution Dynamics of N-Atom Center Reactions: A Study of CH3O- with NH2Cl.

Bimolecular substitution reactions involving N as the central atom have continuously improved our understanding of substitution dynamics. This work used chemical dynamics simulations to investigate the dynamics of NH2Cl with N as the central atom and the multiatomic nucleophile CH3O- and compared these results with the F- + NH2Cl reaction. The most noteworthy difference is in the competition between proton transfer (PT) and the SN2 pathways. Our results demonstrate that, for the CH3O- + NH2Cl system, the PT pathway is considerably more favorable than the SN2 pathway. In contrast, no PT pathway was observed for the F- + NH2Cl system at room temperature. This can be attributed to the exothermic reaction of the PT pathway for the CH3O- + NH2Cl reaction and is coupled with a more stable transition state compared to the substitution pathway. Furthermore, the bulky nature of the CH3O- group impedes its participation in SN2 reactions, which enhances both the thermodynamic and the dynamic advantages of the PT reaction. Interestingly, the atomic mechanism reveals that the PT pathway is primarily governed by indirect mechanisms, similar to the SN2 pathway, with trajectories commonly trapped in the entrance channel being a prominent feature. These trajectories are often accompanied by prolonged and frequent proton exchange or proton abstraction processes. This current work provides insights into the dynamics of N-centered PT reactions, which are useful in gaining a comprehensive understanding of the dynamics behavior of similar reactions.

Facile In Situ Difluoromethylation of Phenols and Thiols Using Ethyl Bromodifluoroacetate and K2CO3

AbstractHerein, we report an efficient method to access difluoromethyl ethers of thiols and phenols using ethyl bromodifluoroacetate and K2CO3. This method demonstrates chemoselective difluoromethylation of thiols and phenols in the presence of amines. The current method also discloses the synthesis of bis(aryloxy)fluoromethane compounds which are least reported in the literature. Mechanistic investigations revealed that the reaction proceeds through a nucleophilic substitution pathway. We strongly believe this protocol would offer an efficient alternative to earlier photocatalyzed or radical-mediated difluoromethylation methods and it has a great potential in the scale-up of pharmaceutical and agrochemical intermediates that possess difluoromethyl group.

A switchable hydrogenation chemoselectivity of biomass platform compounds based on solvent regulation

Selective catalytic conversion of biomass-derived compounds to fuels and fine chemicals serves as a renewable energy pathway for the partial substitution of fossil resources, in which reaction pathway and selectivity control are key issues. Herein, we report a fully exposed Pt clusters immobilized on CoAl mixed metal oxides catalyst (denoted as Ptn/CoAl-MMOs), which exhibits prominent catalytic performance towards liquid phase hydrogenation reaction of furfural (FAL). Noteworthily, the hydrogenation chemoselectivity can be switched among four products via using four different solvents: tetrahydrofurfuryl alcohol (THFA; yield: 91.4%), furfuryl alcohol (FA; yield: 97.7%), 2-methylfuran (2-MF; yield: 92.1%) and furan (FU; yield: 90.8%) are obtained in ethanol, dioxane, isopropanol and n-hexane solvent, respectively. Experimental studies (in situ FT-IR and TPSR-Mass) combined with theoretical calculations (DFT) reveal that solvent molecules exert an essential influence on the adsorption configuration of FAL via changing the solvent-catalyst and/or substrate-catalyst interaction, which ultimately determines the hydrogenation pathway, key intermediate and final product. This work demonstrates a facile solvent-dependent product-switching strategy within one catalytic system, which opens up potential opportunities for tailoring hydrogenation selectivity in liquid-solid catalytic reactions towards biomass upgrading.

High-level ab initio characterization of the OH + CH3NH2 reaction

The complex multichannel OH + CH3NH2 reaction is investigated with high-level ab initio methods considering not just the abstraction, but the substitution pathways, too. The H-abstraction channels are proved to...

Solid state engineering of Bi2S3/rGO nanostrips: an excellent electrode material for energy storage applications.

The study presents a novel, one-pot, and scalable solid-state reaction scheme to prepare bismuth sulphide (Bi2S3)-reduced graphene oxide (rGO) nanocomposites using bismuth oxide (Bi2O3), thiourea (TU), and graphene oxide (GO) as starting materials for energy storage applications. The impact of GO loading concentration on the electrochemical performance of the nanocomposites was investigated. The reaction follows a diffusion substitution pathway, gradually transforming Bi2O3 powder into Bi2S3 nanostrips, concurrently converting GO into rGO. Enhanced specific capacitances were observed across all nanocomposite samples, with the Bi2S3@0.2rGO exhibiting the highest specific capacitance of 705 F g-1 at a current density of 1 A g-1 and maintaining a capacitance retention of 82% after 1000 cycles. The superior specific capacitance is attributed to the excellent homogeneity and synergistic relation between rGO and Bi2S3 nanostrips. This methodology holds promise for extending the synthesis of other chalcogenides-rGO nanocomposites.

A general copper-catalysed enantioconvergent C(sp3)-S cross-coupling via biomimetic radical homolytic substitution.

Although α-chiral C(sp3)-S bonds are of enormous importance in organic synthesis and related areas, the transition-metal-catalysed enantioselective C(sp3)-S bond construction still represents an underdeveloped domain probably due to the difficult heterolytic metal-sulfur bond cleavage and notorious catalyst-poisoning capability of sulfur nucleophiles. Here we demonstrate the use of chiral tridentate anionic ligands in combination with Cu(I) catalysts to enable a biomimetic enantioconvergent radical C(sp3)-S cross-coupling reaction of both racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles. This protocol not only exhibits a broad substrate scope with high enantioselectivity but also provides universal access to a range of useful α-chiral alkyl organosulfur compounds with different sulfur oxidation states, thus providing a complementary approach to known asymmetric C(sp3)-S bond formation methods. Mechanistic results support a biomimetic radical homolytic substitution pathway for the critical C(sp3)-S bond formation step.

Peroxide-Initiated Hydrophosphinylation of gem-Difluoroalkenes.

The installation of fluorine and fluorinated functional groups into drug-like scaffolds can perturb the physicochemical, pharmacokinetic, and pharmacodynamic properties of compounds. However, some potentially useful fluorinated substructures reside predominantly outside the realm of the current synthetic methodologies. One such substructure, the α,α-difluorophosphine oxide, might be convergently prepared by the reaction of a gem-difluorinated alkene with a P-H bond, though such nucleophilic reactions instead proceed through a C-F substitution pathway that delivers monofluorovinyl products. In contrast, we report a peroxide-initiated hydrophosphinylation reaction of gem-difluoroalkenes that avoids C-F substitution and produces a wide range of α,α-difluorophosphine oxides and functions using readily available reagents and green solvents.

CuO Promotes the Formation of Halogenated Disinfection Byproducts during Chlorination via an Enhanced Oxidation Pathway.

Previous studies showed that cupric oxide (CuO) can enhance the formation of trihalomethanes (THMs), haloacetic acids, and bromate during chlorination of bromide-containing waters. In this study, the impact of CuO on the formation kinetics and mechanisms of halogenated disinfection byproducts (DBPs) during chlorination was investigated. CuO does not enhance the formation of DBPs (i.e., 1,1,1-trichloropropanone, chloroform, and trichloroacetaldehyde (TCAL) /dichloroacetonitrile) during chlorination of acetone, 3-oxopentanedioic acid (3-OPA), and aspartic acid, respectively. This indicates that the halogen substitution pathway cannot be enhanced by CuO. Instead, CuO (0.1 g L-1) accelerates the second-order rate constants for reactions of chlorine (HOCl) with TCAL, citric acid, and oxalic acid at pH 8.0 and 21 °C from <0.1 to 29.4, 7.2, and 15.8 M-1 s-1, respectively. Oxidation pathway predominates based on the quantification of oxidation products (e.g., a trichloroacetic acid yield of ∼100% from TCAL) and kinetic modeling. CuO can enhance the formation of DBPs (e.g., THMs, haloacetaldehydes, and haloacetonitriles) during chlorination of model compounds and dissolved organic matter, of which both halogen substitution and oxidation pathways are required. Reaction rate constants of rate-limiting steps (e.g., citric acid to 3-OPA, aromatic ring cleavage) could be enhanced by CuO via an oxidation pathway since CuO-HOCl complex is more oxidative toward a range of substrates than HOCl in water. These findings provide novel insights into the DBP formation pathway in copper-containing distribution systems.

Atmospheric degradation of dimethyl sulfone mediated by [rad]OH, [rad]Cl and NO3[rad], and the C-centered dimethyl sulfone radical + 3O2 reaction: A kinetics and mechanistic study

Mechanistic and kinetics studies of the gas phase reactions of dimethyl sulfone (DMS(O)2; CH3S(O)2CH3) mediated by hydroxyl radical (OH), chlorine atom (Cl) and nitrate radical (NO3) have been extensively investigated using quantum chemistry calculations along with kinetic modeling. The reaction of DMS(O)2 + OH/Cl/NO3 can in principle undergo abstraction and substitution pathways. The results revealed the dominant path to be abstraction of an H-atom from the methyl group of DMS(O)2 by OH, Cl and NO3, with barriers of 2.1, 4.2, and 9.8 kcal mol−1 respectively relative to their starting reactants, to produce CH2S(O)2CH3. The barrier heights for the substitution paths involved in the DMS(O)2 + OH, DMS(O)2 + Cl and DMS(O)2 + NO3 reactions were found to be very high (>30 kcal mol−1) and therefore inaccessible under tropospheric conditions. The rate coefficients for all possible H-atom abstractions associated with the DMS(O)2 + OH, DMS(O)2 + Cl and DMS(O)2 + NO3 reactions were calculated using Master equation solver for multi-energy well reactions (MESMER) code in the temperature range of 200–320 K and 1 atm. The overall rate coefficients for the reaction of DMS(O)2 initiated by OH radical, Cl atom and NO3 radical at 298 K and 1 atm were estimated to be 4.6 × 10−13, 9.1 × 10−14 and 3.7 × 10−15 cm3 molecule−1 s−1, respectively. The atmospheric lifetime of DMS(O)2 with respect to its reactions with OH, Cl and NO3 was also estimated. The major product CH2S(O)2CH3 further reacts with ground state molecular oxygen (3O2) to form the CH3S(O)2CH2OO adduct. Computational methods also showed that the rate of unimolecular isomerization of the CH3S(O)2CH2OO adduct is slow compared to its reactions with NO and hydroperoxyl (HO2) radical. Ultimately, the CH3S(O)2CH2OO adduct leads to formation of formic acid, sulfur dioxide, formaldehyde, methanol, carbon dioxide, sulfene, and OH radical as final products under high NO and HO2 radical atmospheric conditions.

Reactivity and Mechanisms of Methane, Ethane, and Benzene C–H Amination with an Iodine(III) Bistriflimide Complex

The iodine(III) bistriflamide complex (C6F5)IIII(NTf2)2 in HNTf2 (bistriflimide acid; (CF3SO2)2NH) selectively aminates methane and ethane. At a 100 °C reaction with methane after 3 h, it resulted in the exclusive formation of MeNTf2 with a yield of approximately 40%. For ethane, at 100 °C in 2 h, a > 80% yield was found for a combination of monofunctionalized and difunctionalized amination products. In contrast to alkanes giving functionalized products, the reaction of (C6F5)IIII(NTf2)2 with benzene resulted in being stalled at (C6F5)IIII(Ph)(NTf2) with a <5% conversion to PhNTf2 even at 120 °C. PWPB95-D3(BJ) density functional theory calculations indicate that C–H activation is the lowest energy pathway to break the hydrocarbon bonds and is lower in energy than radical, electron-transfer, proton-coupled electron-transfer, or hydride substitution pathways. For methane, from the (C6F5)IIII(CH3)(NTf2) intermediate, there is a one-step amine functionalization mechanism that avoids a carbocation intermediate. For ethane, from the (C6F5)IIII(Et)(NTf2) intermediate, dynamics simulations suggest the possibility of a competitive two-step functionalization pathway that involves a short-lived carbocation intermediate. A reaction coordinate strain analysis provides a straightforward model for understanding the relative reactivity rates for alkyl versus aryl functionalization.