Alkyl Halides Research Articles

ATRP with ppb Concentrations of Photocatalysts.

In atom transfer radical polymerization (ATRP), dormant alkyl halides are intermittently activated to form growing radicals in the presence of a CuI/L/X-CuII/L (activator/deactivator) catalytic system. Recently developed very active copper complexes could decrease the catalyst concentration to ppm level. However, unavoidable radical termination results in irreversible oxidation of the activator to the deactivator species, leading to limited monomer conversions. Therefore, successful ATRP at a low catalyst loading requires continuous regeneration of the activators. Such a regenerative ATRP can be performed with various reducing agents under milder reaction conditions and with catalyst concentrations diminished in comparison to conventional ATRP. Photoinduced ATRP (PhotoATRP) is one of the most efficient methods of activator regeneration. It initially employed UV irradiation to reduce the air-stable excited X-CuII/L deactivators to the activators in the presence of sacrificial electron donors. Photocatalysts (PCs) can be excited after absorbing light at longer wavelengths and, due to their favorable redox potentials, can reduce X-CuII/L to CuI/L. Herein, we present the application of three commercially available xanthene dyes as ATRP PCs: rose bengal (RB), rhodamine B (RD), and rhodamine 6G (RD-6G). Even at very low Cu catalyst concentrations (50 ppm), they successfully controlled PhotoATRP. Well-defined polymers with preserved livingness were prepared under green LED irradiation, with subppm concentrations ([PC] ≥ 10 ppb) of RB and RD-6G or 5 ppm of RD. Interestingly, these PCs efficiently controlled ATRP at wavelengths longer than their absorption maxima but required higher loadings. Polymerizations proceeded with high initiation efficiencies, yielding polymers with narrow molecular weight distributions and high chain-end fidelity. UV-vis, fluorescence, and laser flash photolysis studies helped to elucidate the mechanism of the processes involved in the dual-catalytic systems, comprising parts per million of Cu complexes and parts per billion of PCs.

Synthesis of 2,3-Diperfluoroalkylated Quinoxalines via Selenium-Catalyzed Reductive C-C Coupling of Vicinal Perfluoroalkyl Formimidoyl Chlorides.

A direct and efficient approach to access structurally interesting 2,3-diperfluoroalkylated quinoxalines via selenium-catalyzed reductive C-C construction of vicinal bis(perfluoroalkyl formimidoyl chloride)s has been disclosed. This protocol features the use of easily accessible starting materials, scalability, and a diverse functional group tolerance. Mechanism studies suggested that this reaction may involve an interesting selenium-containing seven-membered-ring intermediate and proceed through an electrocyclization/selenium reductive elimination pathway, which is significantly different from the traditional transition-metal-catalyzed reductive coupling strategies of alkyl halides.

Synthesis and Polymerization of Poly Acryl Imide and One of Their Derivatives Then Curing the Product with Alkyl Halide

The present work involved four steps: First step include reaction of acrylamide ,N-?-Methylen-bis(acryl amide) and N-tert Butyl acryl amide with poly acryloyl chloride in the presence of triethyl amine (Et3N) as catalyst, the second step include homopolymerization of all products of the first step by using benzoyl peroxide(BPO) as initiator in (80-90)Co in the presence of Nitrogen gas(N2). In the third step the poly acrylimide which prepare in second step was convert into potassium salt by using alcoholic potassium hydroxide solution. Fourth step include Alkylation of the prepared polymeric salts in third step by react it with different alkyl halides(benzyl chloride, allylbromide , methyl iodide) by using DMF as solvent for(10-12) hours. Structure Confirmation of all prepared polymers were proved using FT-IR, 1H-NMR and C13-NMR spectroscopy for some polymers. Other physical properties including softening and melting points of the polymers were also measured.

Small Molecule Activation at the acriPNP Pincer-Supported Nickel Sites.

ConspectusNickel pincer systems have recently attracted much attention for applications in various organometallic reactions and catalysis involving small molecule activation. Their exploration is in part motivated by the presence of nickel in natural systems for efficient catalysis. Among such systems, the nickel-containing metalloenzyme carbon monoxide dehydrogenase (CODH) efficiently and reversibly converts CO2 to CO at its active site. The generated CO moves through a channel from the CODH active site and is transported to a dinuclear nickel site of acetyl-coenzyme A synthase (ACS), which catalyzes organometallic C-S and C-C bond forming reactions. An analogous C-S bond activation process is also mediated by the nickel containing enzyme methyl-coenzyme M reductase (MCR). The nickel centers in these systems feature sulfur- and nitrogen-rich environments, and in the particular case of lactate racemase, an organometallic nickel pincer motif revealing a Ni-C bond is observed. These bioinorganic systems inspired the development of several nickel pincer scaffolds not only to mimic enzyme active sites and their reactivity but also to further extend low-valent organonickel chemistry. In this Account, we detail our continuing efforts in the chemistry of nickel complexes supported by acridane-based PNP pincer ligands focusing on our long-standing interest in biomimetic small molecule activation. We have employed a series of diphosphinoamide pincer ligands to prepare various nickel(II/I/0) complexes and to study the conversion of C1 chemicals such as CO and CO2 to value-added products. In the transformation of C1 chemicals, the key C-O bond cleavage and C-E bond (E = C, N, O, or S, etc.) formation steps typically require overcoming high activation barriers. Interestingly, enzymatic systems overcome such difficulties for C1 conversion and operate efficiently under ambient conditions with the use of nickel organometallic chemistry. Furthermore, we have extended our efforts to the conversion of NOx anions to NO via the sequential deoxygenation by nickel mediated carbonylation, which was applied to catalytic C-N coupling to produce industrially important organonitrogen compound oximes as a strategy for NOx conversion and utilization (NCU). Notably, the rigidified acriPNP pincer backbone that enforces a planar geometry at nickel was found to be an important factor for diversifying organometallic transformations including (a) homolysis of various σ-bonds mediated by T-shaped nickel(I) metalloradical species, (b) C-H bond activation mediated by a nickel(0) dinitrogen species, (c) selective CO2 reactivity of nickel(0)-CO species, (d) C-C bond formation at low-valent nickel(I or 0)-CO sites with iodoalkanes, and (e) catalytic deoxygenation of NOx anions and subsequent C-N coupling of a nickel-NO species with alkyl halides for oxime production. Broadly, our results highlight the importance of molecular design and the rich chemistry of organonickel species for diverse small molecule transformations.

Catalytic Asymmetric Barbier Reaction of Ketones with Unactivated Alkyl Electrophiles.

The Barbier reaction is a reductive-type addition of an aldehyde or ketone with an organic electrophile in the presence of a terminal metal reductant, providing a straightforward and efficient method for carbon-carbon bond formation. This reaction possesses the advantage of circumventing the preparation of moisture- and air-sensitive organometallic reagents. However, the catalytic Barbier reaction of ketones to construct tetrasubstituted stereogenic centers is largely underdeveloped, despite its great potential for accessing synthetically challenging chiral tertiary alcohol. Particularly, the leveraging of unactivated alkyl electrophiles as coupling components is still rarely exploited. Herein, we disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones to address the aforementioned challenges, thereby allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. Both types of alkyl electrophiles include primary, secondary, and tertiary ones, thus affording diverse enantioenriched tertiary alcohols with a broad substrate scope. This enantioselective protocol is applied for the expedient synthesis of core structure of Sofdra, a very recent FDA-approved drug in 2024. The newly developed bisoxazolinephosphine (NPN) ligand enables high enantioselectivity in this asymmetric reductive addition process.

Front Cover: Organocatalyzed Carbonylation of Alkyl Halides Driven by Visible Light

Front Cover: Organocatalyzed Carbonylation of Alkyl Halides Driven by Visible Light

Synthesis of Halogen-Substituted [12]Mercuracarborands-4. Crystal Structure of {[(9,12-I<sub>2</sub>-C<sub>2</sub>B<sub>10</sub>H<sub>8</sub>-1,2-Hg)<sub>4</sub>]Cl}Na(H<sub>2</sub>O)<sub>n</sub>

The reactions of the dilithium derivatives of 9,12-dihalogen-ortho-carboranes 1,2-Li2-C2B10H8-9,12-X2 (X = Cl, Br, I) with mercury chloride HgCl2 afford a number of complexes of the chloride ion with the halogen derivatives of [12] mercuracarborand-4: {[(9,12-X2-C2B10H8-1,2ʹ-Hg)4]Cl}Na · nH2O. The molecular crystal structure of the complex of the[12]mercuracarborand-4 octaiodine derivative with the chloride ion is determined by X-ray diffraction. The substituents at the periphery of the mercury-containing macrocycle are found to exert a substantial effect on the macrocycle geometry leading to the transition from the planar to butterfly conformation, whose geometry is predetermined by a set of intermolecular interactions in the crystal.

Synthesis and structural analysis of 1,4′-pyrazolo[3,4-e][1,4]thiazepin-7′(6H)ones: An example of conformational chirality in seven-membered heterocycles

A series of five new N-alkylspiro[1,4]thiazepin-2-ones was obtained in good yields using a two-step synthesis strategy involving the preparation of the spirothiazepinone core, followed by the N-alkylation using alkyl halides in alkaline conditions. The latter N-alkylation reaction gave rise to conformational chirality, evidenced in NMR spectra, polarimetry, chiral HPLC, and X-ray diffraction analysis. X-ray studies revealed the presence of enantiomorphic boat-type conformers in centrosymmetric unit cells interacting by van der Waals forces, in contrast to a predominant conformer in solution supported by the chiral properties of the N-alkylated derivatives. The present work makes an important contribution to the study of the structural properties of 1,4-thiazepinone systems and the phenomenon of conformational chirality in seven-membered N-heterocycles.

Fabrication and Characterization of Alkyl-Functionalized CNFs/Cellulose Acetate Polymer Nanocomposites

Carbon nanofibers (CNFs) are kwidely used to fabricate nanocomposites with enhanced properties. The emergent properties of the nanocomposites depend on the initial properties of the CNFs and how the fibers have been dispersed within the polymer matrix. This study looks at the fabrication of nanocomposites using dodecyl, butyl, and acetyl functionalized CNFs with cellulose acetate as the polymer matrix. The CNFs were prepared by electro-spinning, and functionalization was achieved using alkyl halides in the presence of lithium. Scanning Electron Microscopy (SEM) showed that the fibers were well embedded in the polymer Matrix, Thermal Gravimetric Analysis (TGA) of the nanocomposite revealed a slight increase in the degradation temperatures of the nanocomposites as compared to the blank sample, the aggregate loss of weight of the samples was about 80%. Dynamic Mechanical Analysis (DMA) of the nanocomposites showed increased stiffness and modulus storage by an average of 450MPa for butyl and dodecyl-functionalized CNFs, however, the storage modulus values of the nanocomposites generally decreased with an increase in temperature. The glass transition temperature of the nanocomposites was higher than that of the reference sample by an average of +36°C. Conductivity measurements of the nanocomposites showed no changes at lower frequencies of 1x10<sup>2</sup> - 4x10<sup>4</sup>Hz. However, the values started increasing at peaked at 5x10<sup>7</sup>Hz. The conductivity measurements revealed that the nanocomposites exhibited higher conductivity peaks at specific frequencies compared to the reference sample, indicating an enhanced electrical property of the nanocomposite. The study successfully fabricated nanocomposites with enhanced mechanical, thermal, and dielectric properties using functionalized CNFs.

Nickel-Catalyzed Enantioselective Alkylation of Primary Phosphines.

Functional molecules derived from stereogenic phosphorus centers have important applications in the discovery of drugs and agrochemicals. They are also widely utilized as chiral ligands or organocatalysts for diverse asymmetric transformations. However, access to P-stereogenic motifs has always been regarded as a highly challenging yet desirable goal in organic synthesis. The development of general and practical methods for the stereoselective construction of synthetically versatile P(III)-stereogenic phosphines is particularly appealing but remains elusive. Herein, we describe a nickel-catalyzed asymmetric alkylation of primary phosphines with alkyl halides for the synthesis of P-stereogenic secondary phosphine-boranes with high enantioselectivity and broad substrate scope. The resulting optically active secondary phosphine-boranes allow for further stereospecific transformations, thereby establishing a modular and efficient platform for the diversity-oriented construction of P-stereogenic phosphine compounds.

An amide-based covalent organic framework chemically anchored on silica nanoparticles for headspace microextraction sampling of halogenated hydrocarbons in air

A needle trap device (NTD) was developed using an amide-based covalent-organic framework (COF), chemically bonded to silica nanoparticles. The NTD was coupled with gas chromatography-flame ionization detection (GC-FID) and employed for the headspace microextraction analysis of halogenated hydrocarbons (HHCs) in the air. The adsorbent was characterized using Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction analysis (XRD), transmission electron microscopy (TEM), and field-emission scanning electron microscopy (FE-SEM) techniques.Optimal values for the experimental variables were assessed using response surface methodology (RSM) with a central composite design (CCD), thereby reducing the number of experiments, material consumption, costs, and time. The optimal values for desorption time and temperature were obtained 5 min and 260 °C, respectively. Breakthrough volume (BtV) was studied over the range of 0.5 - 3 times the occupational exposure limit (OEL) and its optimal value was found to be 1200 mL. The optimal sampling temperature and relative humidity (RH) were obtained 20 °C, and 15 %, respectively. The limits of detection (LODs) and limits of quantification (LOQs) were ranged from 0.013 to 0.077 μg l-1 and 0.041 to 0.21 μg l-1, respectively, with a linear dynamic range (LDR) of 0.04 to 100 μg l-1. The method's repeatability and reproducibility (RSD %) were observed over the ranges of 5.3 - 6.4 % and 4.7 -6.9 %, respectively. A statistically validated agreement was observed between the NTD-GC-FID method and the NIOSH 1003 standard procedure for the sampling and determination of HHCs in real workplace air samples, demonstrating the reliability and accuracy of the developed approach.

C-C Bonding in Molecular Systems via Cross-Coupling-like Reactions Involving Noncovalently Bound Constituent Ions.

Carbon-based molecules are of universal importance for a huge variety of chemical and biological processes. The complication of the structure of such molecules proceeds via the bonding of carbon atoms. An efficient mechanism for such reactions proceeds via cross-coupling, related to the association of bond-terminating counter-ions. Here, an uncommon version of such a process is investigated, with at least some ions bound in the system noncovalently and/or switching the bonding mode in due course. The analyzed sample reactions involve a single C-C bond formation in environmentally relevant halocarbon species and involve alkali-halide ion-pair components. A consistent ab initio computational study predicts the related energy barriers to alter significantly in the presence of the ion pair. Different channels are checked, with the carbon-halogen bond cleavage preceding or following the actual C-C bonding and with the counter-ions located closely or farther apart. The relative heights of the corresponding energy barriers are found to be switched by the ion pair. The above results suggest a possibility of facilitating such reactions without expensive catalysts.

Unveiling the Unique Reactivity of Anionic Mn(I) Complexes via Metal-Ligand Cooperation: Nucleophilic Attack on C(sp3)-X Bonds.

Metal-ligand cooperation (MLC) has emerged as a pivotal strategy for the catalytic activation of small molecules within both synthetic and biological arenas. Leveraging this approach, a suite of potent catalytic reactions─encompassing hydrogenation, hydroelementation, and dehydrogenative processes─have been realized, with notable advances in manganese catalysis in recent years. However, the activation of alkyl halides by Mn complexes, which typically requires strong reductants to form Mn(-I) complexes that are incompatible with standard cross-coupling conditions, remains a significant challenge. This limitation underscores the urgent need to investigate alternative methods for activating C(sp3)-X bonds using higher valence state Mn complexes. In response to this challenge, we present the synthesis, characterization, and reactivity of a new anionic Mn(I) complex featuring a redox-active dianionic ligand that induces multiple MLC functionalities. We have discovered an innovative mechanism of MLC, characterized by a single ligand transferring two electrons to the metal center. This novel process facilitates an orbital-symmetry-allowed nucleophilic attack on C(sp3)-X bonds, preserving manganese's oxidative state at +1. To the best of our knowledge, this is the first instance where the MLC strategy via a two-electron transfer process has been utilized to execute an SN2 nucleophilic attack at a C(sp3)-X bond by a relatively electron-deficient metal center like Mn(I). Additionally, the dianionic ligand of the anionic Mn(I) complex exhibits ambident nucleophilicity by reacting with different electrophiles, further highlighting its versatile reactivity.

Unraveling the Stability and Magnetic Properties of Bis-Hydrated Mn(II) Complexes via Tailored Ligand Design.

Exploring the electronic structure and dynamic behavior of Mn(II) complexes reveals fascinating magnetic properties and prospective biomedical applications. In this study, we investigate the solvent phase dynamics of heptacoordinated Mn(II) complexes through ab initio molecular dynamics simulations and density functional theory (DFT) calculations with effectively varying temperatures. We observed that the complex with high stability ([Mn(pmpa)(H2O)2]) remains relatively rigid as the temperature increases to 90 °C, with only a minor change in its radial distribution functions (RDFs), compared to the RDF peaks at 25 °C. To elucidate the impact of halogens on the magnetic anisotropy of seven-coordinated Mn(II) complexes, we performed both DFT and multireference calculations. This shows that the zero-field splitting (ZFS) parameter D follows the order D(I)> D(Br)> D(Cl). We observed a significant increase in the D-value following the substitution of soft Se-donors in the equatorial position and heavier halogens in the axial position. The D-value of halogen derivatives of Se-analogues varies in the order of D(Cl) < D(I) < D(Br), deviating from the regular spectrochemical series with the discrepancy between the covalency of the Mn(II)-Se bond and the ligand field strength. We anticipate that this study will enhance our understanding of the solvent phase dynamics and structural aspects of ZFS in various Mn(II) complexes with different electronic environments.

Copper-Photocatalyzed Amination of Unactivated Alkyl Halides by Inner-Sphere Single Electron Transfer

Copper-Photocatalyzed Amination of Unactivated Alkyl Halides by Inner-Sphere Single Electron Transfer

Radical Replacement Process for Ligated Boryl Radical-Mediated Activation of Unactivated Alkyl Chlorides for C(sp3)-C(sp3) Bond Formation.

The ligated boryl radical (LBR) has emerged as a potent tool for activating alkyl halides in radical transformations through halogen-atom transfer (XAT). However, unactivated alkyl chlorides still present an open challenge for this strategy. We herein describe a new activation mode of the LBR for the activation of unactivated alkyl chlorides to construct a C(sp3)-C(sp3) bond. Mechanistic studies reveal that the success of the protocol relies on a radical replacement process between the LBR and unactivated alkyl chloride, forming an alkyl borane intermediate as the alkyl radical precursor. Aided with the additive K3PO4, the alkyl borane then undergoes one-electron oxidation, generating an alkyl radical. The incorporation of the radical replacement activation model to activate unactivated alkyl chlorides significantly enriches LBR chemistry, which has been applied to activate alkyl iodides, alkyl bromides, and activated alkyl chlorides via XAT.

Redox Activity and Potentials of Bidentate N-Ligands Commonly Applied in Nickel-Catalyzed Cross-Coupling Reactions.

Bidentate N-ligands are paramount to recent advances in nickel-catalyzed cross-coupling reactions. Through comprehensive organometallic, spectroscopic, and computational studies on bi-oxazoline and imidazoline ligands, we reveal that a square planar geometry enables redox activity of these ligands in stabilizing nickel radical species. This finding contrasts with the prior assumption that bi-oxazoline lacks redox activity due to strong mesomeric donation. Moreover, we conducted systematic cyclic voltammetry (CV) analyses of bidentate pyridyl, oxazoline, and imidazoline nitrogen ligands, along with their corresponding nickel complexes. Complexation with nickel shifts the reduction potentials to a more positive region and narrows the differences in redox potentials among the ligands. Additionally, various ligands led to different degrees of bromide dissociation from singly reduced (L)Ni(Ar)(Br) complexes, reflecting varying reactivity in the subsequent activation of alkyl halides, a crucial step in cross-electrophile coupling. These insights highlight the significant electronic effects of ligands on the stability of metalloradical species and their redox potentials, which interplay with coordination geometry. Quantifying the electron-donating, p-accepting properties of these ligands, as well as their effect on catalyst speciation, provides crucial benchmarks for controlling catalytic activity and enhancing catalyst stability.

A General Enantioselective α-Alkyl Amino Acid Derivatives Synthesis Enabled by Cobalt-Catalyzed Reductive Addition.

Enantioenriched unnatural amino acids represent a prevalent motif in organic chemistry, with profound applications in biochemistry, medicinal chemistry, and materials science. Herein, we report a cobalt-catalyzed aza-Barbier reaction of dehydroglycines with unactivated alkyl halides to afford unnatural α-amino esters with high enantioselectivity. This catalytic reductive alkylative addition protocol circumvents the use of moisture-, air-sensitive organometallic reagents, and stoichiometric chiral auxiliaries, enabling the conversion of a variety of primary, secondary, and even tertiary unactivated alkyl halides to α-alkyl-amino esters under mild conditions, thus leading to broad functional group tolerance. The expedient access to biologically active motifs demonstrates the practicality of this protocol by reducing the number of synthetic steps and enhancing the reaction efficiency.

Evaluating the Utility of the MSTI Assay in Predicting Compound Promiscuity and Cytotoxicity.

Nonspecific reactive chemicals often interfere with the interpretation of high-throughput assay results because of their promiscuity and/or cytotoxicity. Using a high-throughput assay to identify such compounds is necessary to efficiently rule out potential assay artifacts. The MSTI, (E)-2-(4-mercaptostyryl)-1,3,3-trimethyl-3H-indol-1-ium, assay uses a thiol-containing fluorescent probe to screen for electrophile reactivity and could potentially be used to determine nonspecific reactive compounds. The Tox21 10K compound library was previously screened against a panel of ∼80 cell-based and biochemical assays, including the biochemical MSTI assay. In this study, we compared the MSTI assay activity of the Tox21 10K compounds with their promiscuity and cytotoxicity as reflected by their activities across the Tox21 assay panel to determine: (1) if this assay is predictive of a compound's promiscuity and cytotoxicity and (2) what chemical features create inconsistent results between the MSTI assay activity and promiscuity/cytotoxicity (false negatives and false positives). We found that the MSTI assay can predict a chemical's promiscuity/cytotoxicity with a 0.55 sensitivity and 0.97 specificity. Out of 3,407 unique compounds evaluated, we identified 92 false positive and 227 false negative results. Several structural features such as carboxamides and alkyl halides were found to be apparent in 53% (p = 2.4 × 10-07) and 19% (p = 4.3 × 10-06) of the false positives and negatives, respectively. The results of this analysis will help identify the potential challenges of this high-throughput assay and allow researchers to identify if a compound will be cytotoxic or promiscuous in an efficient manner.

Defluorinative Haloalkylation of Unactivated Alkenes Enabled by Dual Photoredox and Copper Catalysis.

A three-component defluorinative haloalkylation of alkenes with trifluoromethyl compounds and TBAX (X = Cl, Br) via dual photoredox/copper catalysis is reported. The mild conditions are compatible with a wide array of activated trifluoromethyl aromatics bearing diverse substituents, and various nonactivated terminal and internal alkenes, enabling straightforward access to synthetically valuable γ-gem-difluoroalkyl halides with high efficiency. Mechanistic studies indicate that the [Cu] complexes not only serve as XAT catalysts but also facilitate the SET reduction of trifluoromethyl groups by photocatalysts. Additionally, the resulting alkyl halide products can serve as versatile conversion intermediates for the synthesis of a diverse range of γ-gem-difluoroalkyl compounds.