Alkylation Reactions Research Articles

In Situ Synthesis of Hypercrosslinked Polymer as Stationary Phase for Capillary Gas Chromatography

Hypercrosslinked polymers (HCPs) constructed by the Friedel–Crafts alkylation reaction of aromatic compounds have emerged as a new class of porous materials with unique merit. Herein, a HCP named HCP-TPB was coated onto a capillary column through in situ synthesis. The prepared column exhibited a nonpolar nature, and the column efficiency for n-dodecane was 3003 plates m−1. Moreover, the relative standard deviations of retention time and peak area for six replicate injections of the C3–C6 were lower than 0.1% and 1.5%, respectively. The results of this study showed that it is very promising to utilize HCPs as stationary phases for the separation of C3–C6.

Pnictogen and Chalcogen Salts as Alkylating Agents.

Alkylation reactions and their products are considered crucial in various contexts. Synthetically, the alkylation of a nucleophile is usually promoted using hazardous alkyl halides. Here, we aim to highlight the potential of pnictogen (ammonium or phosphonium) and chalcogen salts (sulfonium, selenonium, and telluronium) to function as alkylating agents. These compounds can be considered as non-volatile electrophilic alkyl reservoirs. We will center our discussion on the strategies developed in recent years to expand the synthetic utility of these salts in terms of transferable alkyl groups, substrate scope, and product selectivity.

Rhodium(III)-Catalyzed Regioselective C-H Alkenylation and Alkylation of Menadione Analogues with β-Trifluoromethyl Enones.

Menadione and its structural analogues are important motifs present in various bioactive natural products and drugs with a wide range of biological activities. In addition, β-trifluoromethyl enone has been employed as an efficient fluorinated building block for the synthesis of CF3-containing organic scaffolds. Herein, we report both C-H alkenylation and C-H alkylation reactions using β-CF3 enones as coupling partners with amino-substituted menadiones under Rh(III) catalysis. While β-CF3 enones have been studied in C-H alkylation reactions, we herein for the first time disclose the Rh (III)-catalyzed C-H alkenylation reaction of β-CF3 enones. The presence of an oxidant was crucial for the alkenylation reaction with β-CF3 enone. Meanwhile, the alkylation reaction proceeds via redox-neutral conditions.

Aromatics Alkylated with Olefins Utilizing Zeolites as Heterogeneous Catalysts: A Review

The alkylation reaction of aromatic compounds gains considerable attention because of its wide application in bulk and fine chemical production. Aromatics alkylated with olefins is a well-known process, particularly for linear alkylbenzene, phenyloctanes, and heptyltoluene production. As octane boosters and precursors for various petrochemical and bulk chemical products, a wide range of alkylated compounds are in high demand. Numerous unique structures have been proposed in addition to the usual zeolites (Y and beta) utilized in alkylation procedures. The inevitable deactivation of industrial catalysts over time on stream, which is followed by a decrease in catalytic activity and product selectivity, is one of their disadvantages. Therefore, careful consideration of catalyst deactivation regarding the setup and functioning of the process of catalysis is necessary. Although a lot of work has been carried out to date to prevent coke and increase catalyst lifespan, deactivation of the catalyst is still unavoidable. Coke deposition can lead to catalyst deactivation in industrial catalytic processes by obstructing pores and/or covering acid sites. It is very desirable to regenerate inactive catalysts in order to remove the coke and restore catalytic activity at the same time. Depending on the kind of catalyst, the deactivation processes, and the regeneration settings, each regeneration approach has pros and cons. In this comprehensive study, the focus was on discussing the reaction mechanism of 1-octene isomerization and toluene alkylation as an example of isomerization and alkylation reactions that occur simultaneously, shedding light in detail on the catalysts used for this type of complex reaction, taking into account the challenges facing the catalyst deactivation and reactivation procedures.

Synthesis of α-Boryl-α-Substituted Allylboronates from Propyne.

A novel method for the two-step synthesis of α-boryl-α-substituted allylboronates from propyne is described. These allylboronates are prepared by the Co-catalyzed 1,1-diboration reaction of propyne with B2pin2, followed by the base-mediated alkylation reaction of 1,1-di(boryl)propene at the α-position. Computational studies revealed the origins of observed reactivity and selectivity in the base-mediated alkylation reaction. The resulting α-boryl-α-methyl-allylboronate is applied to the allylation of aldehydes, which gives homoallylic alcohols with a trisubstituted alkene moiety.

Design, synthesis, and anti-breast cancer activity evaluation of novel 3-cyanopyridine derivatives as PIM-1 inhibitors.

A novel series of cyanopyridines 7a-j were synthesized via a one-pot multicomponent reaction of arylidene 4 with ammonium acetate 5 and respective methylaryl/heterylketones 6a-j in ethanol using vanillin as a natural starting material. Moreover, the regioselective alkylation reaction was studied by the treatment of cyanopyridines 7a-f and 7j with CH3I in the presence of K2CO3 in DMF to afford O-methylcyanopyridines 8a-g (major) and N-methylcyanopyridines 9a-g (minor), whereas bipyridine 7h gave bipyridinium iodide salt 10. All of the designed cyanopyridines were evaluated as anti-breast cancer (MCF-7) cell lines via PIM Kinase inhibitory activity, and the results displayed that some of them showed high activities, especially compounds 7h and 8f, which showed excellent activities against MCF-7 with IC50 values of 1.89 and 1.69 μM, respectively, more potent than the reference drug doxorubicin. Mechanistically, compounds 7h and 8f exhibited strong in vitro PIM-1 kinase inhibitory activity with an IC50 of 0.281 and 0.58 μM, respectively, compared to the reference staurosporine. Moreover, compound 7h arrested the tumor cells at the S phase and caused cell death mainly by inducing early and late apoptosis. Molecular docking studies against PIM-1 revealed good binding modes of the synthesized compound and showed agreement with the biological results.

Combining the Nonnatural Activity of Lipase and Electrocatalysis in One Pot: Sustainable and Regioselective Synthesis of C‐3 Alkylated Oxindoles

AbstractIn this study, we report an environment‐friendly protocol by integrating the nonnatural catalytic activity of lipase with electrocatalysis for synthesizing C‐3 alkylated oxindoles, which are part of many natural and pharmaceuticals products. Gratifyingly, Candida antarctica lipase B (CALB) is found to be highly active and regioselective for catalyzing the nonnatural C‐3 alkylation reaction at indole when combined with an electrochemical C‐2 oxidation process in the same vessels. Further, the generality and feasibility of the developed protocol are shown by employing several functional groups on the indole moiety and obtaining the desired products in moderate to good yield. Besides, the control experiments are set up along with the molecular docking studies to substantiate the role of the active site of Candida antarctica lipase B (CALB) in carrying out the regioselective C‐3 alkylation reaction. In addition, control experiments and cyclic voltammetry are performed to get insight into the electrochemical C‐2 oxidation process and as a result, a plausible mechanism for the integrated process is presented.

Chalcogen Bond-Driven Alkylations: Selenoxide-Pillar[5]arene As A Recyclable Catalyst For Displacement Reactions In Water.

A novel strategy to catalyze alkylation reactions through chalcogen bond interaction using a supramolecular structure is presented herein. Utilizing just 1.0 mol% of selenoxide-pillar[5]arene (P[5]SeO) as the catalyst we achieved efficient catalysis in the cyanation of benzyl bromide in water. Our approach demonstrated high efficiency and effectiveness, with the results supported by designed control experiments and theoretical models, highlighting the catalytic effect of the pillar[5]arene through noncovalent interactions. Quantum-chemical calculations (ωB97X-D/def2-TZVP@SMD) pointed out that the catalyzed cyanation reaction followed an SN2-like mechanism, with energy barriers (ΔH‡) ranging from 16.7 to 18.2 kcal mol-1, exhibiting dissociative character depending on the para-substituent. 1H NMR analysis revealed that P[5]SeO acted as a catalyst through inclusion complex formation, facilitating the transfer of the electrophilic substrate to the aqueous solution for nucleophilic displacement. Our reaction protocol proved applicable to various substrates, including aromatic and alpha-carbonyl derivatives. The use of sodium azide as the nucleophile was also feasible. Importantly, our method allowed scalability, and the catalyst P[5]SeO could be recovered and reused effectively for multiple reaction cycles, showcasing sustainability.

Artificial Light-Harvesting Systems with a Three-Step Sequential Energy Transfer Mechanism for Efficient Photocatalytic Minisci-Type Late-Stage Functionalization.

The natural process of photosynthesis involves a series of consecutive energy transfers, but achieving more steps of efficient energy transfer and photocatalytic organic conversion in artificial light-harvesting systems (ALHSs) continues to pose a significant challenge. In the present investigation, a range of ALHSs showcasing a sophisticated three-step energy transfer mechanism is designed, which are meticulously crafted using pillar[5]arene (WP[5]) and p-phenylenevinylene derivative (PPTPy), utilizing host-guest interactions as energy donors. Three distinct types of fluorescent dyes, namely Rhodamine B (RhB), Sulforhodamine 101 (SR101), and Cyanine 5 (Cy5), are employed as acceptors of energy. Starting from PPTPy-2WP[5], energy is sequentially transferred to RhB, SR101, and Cy5, successfully constructing a multi-step continuous energy transfer system with high energy transfer efficiency. More interestingly, as energy is progressively transferred, the efficiency of superoxide anion radical (O2 •-) generation gradually increased, while the efficiency of singlet oxygen (1O2) generation decreased, achieving the transformation from type II photosensitizer to type I photosensitizer. Furthermore, in order to fully utilize the energy harvested and reactive oxygen species (ROS) obtained, the ALHSs employ a multi-step sequential energy transfer process to enhance Minisci-type alkylation reactions with aldehydes through photocatalysis for late-stage functionalization in an aqueous environment, achieving a 91% yield.

Chitosan-grafted Cyclodextrin via Click Chemistry as an Encapsulating Agent to Enhance the Antibacterial Activity of Thymol

Introduction: This paper aimed to investigate, for the first time, the possibility of increasing the antibacterial activities of thymol (TH) by developing an encapsulating agent based on chitosan-grafted cyclodextrin. For this purpose, β-cyclodextrin was monosubstituted at position 6 via propargyl bromide, and chitosan’s amine groups were converted to azide functions. After alkylation and diazotization reactions, the grafting of β-cyclodextrin onto the chitosan (CSβCD) was realized via click chemistry alkyne–azide cycloaddition. Methods: The incorporation of TH into chitosan-grafted β-cyclodextrin (TH/CS-βCD) was performed by the freeze-drying method, and the encapsulation efficiency was investigated based on various mass ratios (TH:CS-βCD). The optimized inclusion complex was then thoroughly examined by scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Results: The antibacterial activity was assessed against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis using broth-microdilution assay. Fourier transform infrared spectroscopy analysis demonstrated the successful grafting of β-cyclodextrin onto chitosan since the optimum mass ratio between TH and CS-βCD was 1:8 (w:w), corresponding to 78 ± 3.42% of encapsulation efficiency, while SEM, XRD, TGA and DSC confirmed the establishment of TH/CS-βCD inclusion complexes. Conclusion: The in vitro investigation showed that TH/CS-βCD exhibited higher antibacterial properties compared to TH in free form.

COSMO-RS prediction, experimental investigation, and mechanism analysis: A new approach to separating the n-hexane–tert-butanol azeotropic system via liquid-liquid extraction with ionic liquids

n-Hexane and tert-Butanol (TBA) are frequently utilized to refine the conditions for Grignard, Wittig, and Friedel-Crafts alkylation reactions. During the synthesis of loratadine, the formation of azeotropic mixtures n-hexane and TBA, which are challenging to separate through conventional distillation, is inevitable. This study utilizes the COSMO-RS model to identify suitable ionic liquids (ILs) for the separation of the n-hexane–TBA azeotropic system. Based on solvent capacity and selectivity, 1-ethyl-3-methylimidazolium trifluoroacetate ([EMIM][TFA]), 1-butyl-3-methylimidazolium trifluoroacetate ([BMIM][TFA]), and 1-hexyl-3-methylimidazolium trifluoroacetate ([HMIM][TFA]) were selected as extractants. The liquid–liquid equilibrium (LLE) data for the n-hexane–TBA – ILs ternary system were measured at 303.15 K and atmospheric pressure. Distribution coefficients and selectivity were calculated to evaluate the performance of the extractants, with the NRTL model used to correlate the experimental LLE data. The consistency of the NRTL model parameters was corroborated through topological analysis associated with the Gibbs tangent principle. Quantum chemical calculations, including interaction energy, ESP analysis, IGMH analysis, and QTAIM topological analysis, were performed to explore the separation mechanism at the molecular level. The results indicated that the interaction energies between the ILs and TBA were higher than those between the ILs and n-hexane, indicating a stronger attraction of ILs to TBA. Consequently, the ILs effectively separated TBA from the n-hexane–TBA azeotropic system, with extraction capacities ranked as [EMIM][TFA] > [BMIM][TFA] > [HMIM][TFA]. The quantum chemical calculations successfully explained the experimental results, aligning with COSMO-RS model predictions and confirming their reliability. IGMH and QTAIM topological analyses systematically explored the types and strengths of interactions, revealing that hydrogen bonds are predominant between the ILs and TBA, with additional contributions from van der Waals forces. Furthermore, the hydrogen bond strengths between TBA and the anions and cations of the ILs are classified as strong and moderate, respectively. This work provides valuable insights into the separation of azeotropic systems using ILs, elucidating the underlying mechanisms behind this process.

Direct C3-H Alkylation and Alkenylation of Quinolines with Enones.

Conversion of quinoline C-H bonds into C-C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, direct alkylation and alkenylation at C3-H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3-H alkylation and alkenylation reactions, exhibiting exceptional regio- and stereoselectivity, all achieved under redox-neutral and transition-metal-free conditions. The method involves a three-step, one-pot or two-pot sequence, including 1,4-dearomative addition, functionalization at C3, and elimination or transalkylation to produce 3-alkylated/alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, and simple alkyl derivatives.

Direct C3−H Alkylation and Alkenylation of Quinolines with Enones

AbstractConversion of quinoline C−H bonds into C−C bonds is essential for obtaining the enormous array of derivatives required for pharmaceutical and agrochemical development. Despite over a century of synthetic efforts, direct alkylation and alkenylation at C3−H positions in a wide array of quinoline precursors remain predominantly challenging and elusive. This report outlines the first successful quinoline C3−H alkylation and alkenylation reactions, exhibiting exceptional regio‐ and stereoselectivity, all achieved under redox‐neutral and transition‐metal‐free conditions. The method involves a three‐step, one‐pot or two‐pot sequence, including 1,4‐dearomative addition, functionalization at C3, and elimination or transalkylation to produce 3‐alkylated/alkenylated quinolines. The presence of a carbonyl group in these products allows for further synthetic manipulations, enabling the production of cyanides, amides, amines, and simple alkyl derivatives.

Copper‐Catalyzed C(sp3)‐H α‐Acetylation: Generation of Quaternary Centers

α‐substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the α‐acetylation of C(sp3)‐H substrates R‐H with arylmethyl ketones ArC(O)Me to provide α‐alkylated ketones ArC(O)CH2R at RT with tBuOOtBu as oxidant via copper(I) β‐diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α‐substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [CuII](CH2C(O)Ar) that capture alkyl radicals R• to give R‐CH2C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4‐diketone ArC(O)CH2CH2C(O)Ar.

Copper-Catalyzed C(sp3)-H α-Acetylation: Generation of Quaternary Centers.

α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the α-acetylation of C(sp3)-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH2R at RT withtBuOOtBu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [CuII](CH2C(O)Ar) that capture alkyl radicals R• to give R-CH2C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH2CH2C(O)Ar.

Engineering of Active Sites in Metal‐Organic Frameworks for Friedel–Crafts Alkylation

AbstractFriedel–Crafts alkylation reaction is one of the C─C bond forming reactions catalyzed by homogeneous or heterogeneous catalysts possessing Lewis and Bronsted acids. Metal organic frameworks (MOFs) with Lewis acid/Bronsted acid sites or hydrogen bonding donor sites are potential catalysts to promote the widely employed Friedel–Crafts alkylation to form C─C bonds between arenes and electron‐poor olefins, alcohols, or alkyl bromides. Such acid‐active sites are present either at the organic linkers or inorganic clusters of the crystalline porous framework, resulting in well‐dispersed heterogeneous active sites able to compete with well‐established homogeneous minerals and organocatalysts. The available literature data are grouped based on the nature of active sites. Whenever possible, the comparison of the activity of MOFs with other heterogeneous and homogeneous catalysts is provided to illustrate the possible benefits of MOFs compared to other catalysts. The concluding section provides our views and future developments in this field.

Doping In Vivo Alkylation in E. coli by Introducing the Direct Sulfurylation Pathway of S. cerevisiae

AbstractMethylation and alkylation are important techniques used for the synthesis and derivatisation of small molecules and natural products. Application of S‐adenosylmethionine (SAM)‐dependent methyltransferases (MTs) in biotechnological hosts such as Escherichia coli lowers the environmental impact of alkylation compared to chemical synthesis and facilitates regio‐ and chemoselective alkyl chain transfer. Here, we address the limiting factor for SAM synthesis, methionine supply, to accelerate in vivo methylation activity. Introduction of the direct sulfurylation pathway, consisting of O‐acetylhomoserine sulfhydrolase (ScOAHS) and O‐acetyltransferase (ScMET2), from S. cerevisiae into E. coli and supplementation with methanethiol or the corresponding disulfide improves atom‐economic methylation activity in three different MT reactions. Up to 17‐fold increase of conversion compared to the sole expression of the MT and incorporation of up to 79 % of the thiol compound added were achieved. Promiscuity of ScOAHS allowed in vivo production of methionine analogues from organic thiols. Further co‐overproduction of a methionine adenosyltransferase yielded SAM analogues which were further transferred by MTs onto different substrates. For methylation of non‐physiological substrates, conversion rates up to 73 % were achieved, with an isolated yield of 41 % for N‐methyl‐2,5‐aminonitrophenol. The here described technique enables E. coli to become a biotechnological host for improved methylation and selective alkylation reactions.

Redox-Neutral, Iron-Mediated Directed C-H Activation: General Principles and Mechanistic Insights.

Experimental and computational studies have been conducted and established the general principles for enabling redox-neutral C-H activation by iron(II) complexes. The idealized octahedral iron(II) dimethyl complex, (depe)2Fe(CH3)2 (depe = 1,2-bis(diethylphosphino)ethane) promoted the directed, regioselective ortho C(sp2)-H methylation of pivalophenone. The rate of the iron(II)-mediated C(sp2)-H functionalization depended on the lability of L-type phosphine ligands, the spin state of the iron center, and the size of the X-type ligands (halide, hydrocarbyl) in P4FeIIX2 complexes. The C(sp2)-H alkylation reaction proved general among multiple substrates with directing groups including carbonyl, imines and pyridines. Among these, ketones and aldehydes were identified as optimal and were compatible with various steric environments and presence of acidic α-hydrogens. With stronger nitrogen donors, higher barriers for product-forming reductive elimination were observed. The effect of orbital hybridization on the chemoselectivity of C-H activation through a σ-CAM pathway by dn>0 transition metals was also established by studying the stoichiometric reactivity of the differentially substituted (depe)2Fe(Me)R complexes (R = alkyl, aryl), where the Fe-R bond with greater s-character preferentially promoted selective C-H activation. Deuterium labeling and kinetic studies, coupled with computational analysis, supported a pathway involving phosphine dissociation and rate-determining C-H bond activation, leading to the observed products.

Visible-light-driven Fe-catalyzed alkylation for synthesizing functionalized polyolefin elastomers as advanced encapsulants in photovoltaic modules

Polyolefin elastomer (POE) has emerged as a promising encapsulant for photovoltaic modules, attributed to its exceptional water vapor barrier properties, robust weather resistance, and enhanced anti-potential induced degradation (anti-PID) capabilities. Despite these advantages, the interfacial adhesion of POE remains a significant challenge, particularly its suboptimal bonding with glass and solar cells, which impedes its broader application within the photovoltaic industry. This study introduced glycidyl methacrylate (GMA) monomers into POE through a photo-induced iron-catalyzed alkylation reaction, developing a novel polyolefin encapsulant for photovoltaic modules. The encapsulant was designed to possess high light transmittance, enhanced adhesion, and elevated resistivity. The modified POE boasts an impressive light transmittance nearing 98% and an adhesive strength of 28.3 N cm−1, both superior to traditional ethylene-vinyl acetate copolymer (EVA) materials. Additionally, this work delves into the correlation between crystallization behavior and light transmittance, elucidating the influence of GMA incorporation on the adhesion and insulation properties of POE through gaussian simulations.

A N-heterocyclics induced π-π interaction strategy to synthesis hyper-crosslinked polymers with enhanced porosity for xenon adsorption

Hyper-crosslinked polymers (HCPs) with large specific surface areas play an important role in gas adsorption and separation. However, the method to enhance the specific surface area of HCPs and gas adsorption performance without changing the polyaromatic hydrocarbons (PAHs) monomer structure and reaction condition is still missing. Here, we present a general and facile N-heterocyclics induced π-π interaction strategy to increase the specific surface area of HCPs by simply adding N-heterocyclics during the Friedel-Crafts alkylation reaction. The specific surface areas of HCP (tetraphenylmethane based HCPs, TPMBPy-TCM) increased up to 7.78 times compared to the one without adding N-heterocyclics. The crosslinking and stacking of PAHs was influenced by the π-π stacking between the N-heterocyclic complexes and PAHs. More importantly, N-heterocyclics coordinated with Lewis acids have lower electron density and do not react with PAHs in the Friedel-Crafts alkylation reaction, which can be removed easily from HCPs. The HCPs obtained shown good xenon adsorption performance with Xe uptake of 3.63 mmol/g, which is the highest value for organic adsorbents reported in literature. This work provides new insight into the preparation of high-performance HCPs.