Nucleophilic Substitution Research Articles

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.

Amide Functionalized Novel Pyrrolo-pyrimidine Derivative as Anticancer Agents: Synthesis, Characterization and Molecular Docking Studies.

The development of new therapies targeting crucial kinases involved in cancer progression is a promising area of research. Pyrazolo pyrimidine derivatives have emerged as potential candidates for this purpose. This study aims to synthesize pyrazolo pyrimidine derivatives (5a-5r), evaluate their molecular docking against key kinases, and assess their anticancer activity. The synthesis involved a multi-step procedure starting with the cyclization of 6-amino-2- methylpyrimidin-4(3H)-one (1) to form 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-ol (2). This was followed by chlorination to yield 4-chloro-2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine (3) and nucleophilic substitution to produce 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-amine (4). The final derivatives (5a-5r) were synthesized through amide bond formation with various carboxylic acids using DCC and DMAP. Structural elucidation was confirmed via NMR, mass spectrometry, and HRMS. Molecular docking studies were conducted against Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and cyclin-dependent kinase 4 (CDK4). Anticancer activity was evaluated against MCF-7, SET-2, and HCT-116 cell lines. Structural elucidation confirmed the successful synthesis of the derivatives. Molecular docking studies revealed promising binding affinities for selected derivatives, particularly those with heterocyclic substitutions. Anticancer activity evaluation showed diverse potency profiles, with several derivatives demonstrating IC50 values comparable to the reference drug, doxorubicin. Derivatives featuring nitro and heterocyclic moieties exhibited significant anticancer activity. The synthesized pyrazolo pyrimidine derivatives showed potential as lead compounds for further development due to their promising binding affinities and significant anticancer activity, particularly those with nitro and heterocyclic moieties.

Tuning Tetramethoxy-acridiniums for Fluorophores and Organic Photoredox Catalysis.

Tetramethoxy substituted alkyl-acridiniums are readily available by facile nucleophilic aromatic substitution on tris(dimethoxyphenyl)carbenium, but are non-fluorescent, presumably due to intramolecular photoinduced electron transfer quenching. In this work we introduce electron withdrawing groups by electrophilic aromatic substitution reactions, leading to fluorescence turn-on. The acridiniums are moderately fluorescent (ϕf = 20%) with long fluorescene lifetimes (τf = 9 ns). The positive excited state reduction potentials (E*red = +1.6 V) make the TMAcr+ excellent electron acceptors in the excited state, and efficient reductive photoredox catalysts able to oxidize a broad range of substrates.

Synthesis of Aminodiborane through the Reaction of Ammonia Borane with Acids.

A facile method for the synthesis of aminodiborane (NH2B2H5, ADB) has been developed through the reaction of ammonia borane (NH3BH3, AB) with an ether solution of hydrogen chloride (HCl·Et2O) at room temperature. In addition, N-alkyl substituted ADB derivatives were synthesized by reacting N-alkyl substituted AB with HCl·Et2O at 50 °C. The mechanistic studies indicated that the nucleophilic substitution reaction of the B-H bonding pair electrons and the dihydrogen bonding interaction play an important role. This work paves an alternative way to prepare amine borane compounds.

Poly(arylene ether)s via Cu(II)-Catalysis.

Poly(arylene ether)s (PAEs) are a versatile class of thermoplastic materials with commercial importance. Currently their synthesis relies predominantly on either nucleophilic or electrophilic aromatic substitution reactions, severely limiting the scope of available PAEs. Herein, we report the copper(II)-catalyzed polycondensation of electronically unactivated aryl bromides with bisphenols to afford a wide range of new PAEs. These PAEs are characterized by their thermal and mechanical properties. Functional PAEs were produced that have reversible acid- and redox-triggered chromophores incorporated into the backbone, which illustrates the utility of these methods.

Intermolecular Ipso Aromatic Nucleophilic Substitution of Electron‐Deficient Aryl Sulfonyl Chlorides

AbstractA mild and efficient approach is described for generating substitution products of electron‐deficient benzenesulfonyl chlorides via intermolecular ipso aromatic nucleophilic substitution reaction. Various amines and thiols effectively undergo a transition‐metal‐free coupling process, leading to diaryl or arylalkyl amines and thioethers with the formation of C─N and C─S bonds. The regioselective attack of N‐nucleophiles produces sulfonamides in the absence of a base. This reaction generates the Smiles rearrangement products. However, a series of mechanistic investigations point toward the intermolecular pathway in contrast to the intramolecular ipso substitution, known as Smiles rearrangement.

Functional Hexafluoroisopropyl Group Used in the Construction of Biologically Important Pyrimidine Derivatives.

A series of versatile 4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)pyridine intermediates have been developed to efficiently produce biaryls, amines, ethers, and thioethers. These hydrolysis-stable ether intermediates exhibit reactivity toward electron-donating groups and nucleophiles in cross-coupling and nucleophilic substitution reactions while surpassing the stability of corresponding aryl halides. In comparison to conventional coupling methods, this protocol offers an alternative pathway for accessing natural product and drug-like compounds without the need for metal catalysts. With assistance of this approach, we successfully obtained a potent P-glycoprotein inhibitor 4k (YS-370), a potent epidermal growth factor receptor inhibitor 4l (YS-363), and a promising lysine-specific demethylase 1 inhibitor 5g.

Photoinduced Intramolecular C−N Coupling For The Synthesis Of Azolo[1,2,4]Benzothiadiazines Derivatives

AbstractThis paper explores an original synthesis of novel heterocyclic compounds derived from photoinduced intramolecular coupling reactions, involving the formation of C−N and C−C bonds. Specifically, two classes of compounds were targeted: 4H‐benzo[e]pyrazolo[1,5‐b][1,2,4]thiadiazines and 5‐amino‐6‐thia‐4,5a‐diazaacephenanthrylenes. The synthetic strategy involved nucleophilic substitution reactions to prepare key sulfonamide starting substrates, followed by photoinduced cyclization (via the Substitution Radical Nucleophilic Unimolecular, SRN1) under mild conditions using visible light. The scope of the reaction was explored with different substituent groups on the starting materials, which demonstrated moderate to very good product yields, with 13 examples and yields of up to 78 %. Moreover, this strategy represents the first synthetic approach to obtain 5‐amino‐6‐thia‐4,5a‐diazaphenanthrylenes.

New Pd(II)-pincer type complexes as potential antitumor drugs: synthesis, nucleophilic substitution reactions, DNA/HSA interaction, molecular docking study and cytotoxic activity.

Two new complexes of Pd(II), [Pd(L1)Cl]Cl (Pd1) and [Pd(L2)Cl]Cl (Pd2), (where L1 = N2,N6-bis(5-methylthiazol-2-yl)pyridine-2,6-dicarboxamide and L2 = N2,N6-di(benzo[d]thiazol-2-yl)pyridine-2.6-dicarboxamide) were synthesized. Characterization of the complexes was performed using elemental analysis, IR, 1H NMR spectroscopy and MALDI-TOF mass spectrometry. The nucleophilic substitution reactions of complexes with L-Methionine (L-Met), L-Cysteine (L-Cys) and guanosine-5'-monophosphate (5'-GMP) were studied by stopped-flow method at physiological conditions (pH = 7.2 and 37 °C). Complex Pd1 was more reactive than Pd2 in all studied reactions, while the order of reactivity of the selected ligands was: L-Met > L-Cys > 5'-GMP. The interaction of complexes with calf thymus-DNA (CT-DNA) was studied by Uv-Vis absorption and fluorescence emission spectroscopy. Competitive binding studies with intercalative agent ethidium bromide (EB) and minor groove binder Hoechst 33258 were performed as well. Both complexes interacted with DNA through intercalation and minor groove binding, where the latter was preferred. Additionally, the interaction of Pd1 and Pd2 complexes with human serum albumin (HSA) was studied employing fluorescence quenching spectroscopy. The results indicate a moderate binding affinity of complexes, with slightly stronger binding of the Pd1. Fluorescence competition experiments with site-markers (eosin Y and ibuprofen) for HSA were used to locate the binding site of Pd1 to the HSA. Additionally, the interaction with DNA and HSA was studied by molecular docking and the revealed results were in good agreement with the experimentally obtained ones. Pd1 complex exhibited cytotoxicity toward human (HCT116) and mouse cell lines (CT26) of colorectal cancer, mouse (4T1) and human (MDA-MB468) breast cancer lines and non-cancerous mouse mesenchymal stem cells (mMSC). In addition, Pd1 complex demonstrated significant selectivity towards cancer cells over non-cancerous mMSC, indicating a high potential to eliminate malignant cells without affecting normal cells. It induced apoptosis in CT26 cells, effectively arrested the cell cycle in the S phase, and selectively down-regulated cyclin D and cyclin E. Moreover, it can alter the expression of cell cycle regulators by increasing p21 and decreasing p-AKT. These findings confirm its ability to disrupt key tumor cell survival signals and suggest that the Pd1 complex is a potent candidate for effective cancer treatment.

Computational investigation of water as catalyst and solvent in aromatic nucleophilic substitution reaction of 2-bromopyridine

Computational investigation of water as catalyst and solvent in aromatic nucleophilic substitution reaction of 2-bromopyridine

Kinetic, Spectral and Mechanistic Regularities of New Reaction Systems With Chromogenic SN2‐Type Reaction for Detection of Epoxy Compounds

ABSTRACTNew reaction systems “oxirane – nucleophile X– – proton‐donor reagent AH – solvent” have been proposed for the detection of epoxides in which nucleophilic opening of the oxirane ring occurs accompanied by the formation of a colored product. The kinetic and mechanistic regularities of reactions in the proposed systems were investigated. Reaction orders with respect to the components of the systems have been determined: close to 1 – for oxirane and X−, close to 0 – for AH. It was shown that the proposed chromogenic reactions represent nucleophilic substitution of SN2‐type and allow the detection of epoxides containing both a terminal and internal epoxy group, which can be used to monitor processes in systems where epoxides are either the initial compounds or the synthesis products. Based on the conducted studies, it is possible to develop methods for the quantitative determination of epoxides using kinetic methods of analysis and UV–visible spectroscopy.

Synthesis of Double Benzimidazole‐Fused Quinazolines and Pyrimidines Catalyzed by Recyclable Magnetic Cu‐MOF‐74

Abstract2‐(2‐Bromoaryl)‐ and 2‐(2‐bromovinyl)benzimidazoles are combined and cyclized with benzimidazoles using a catalytic amount of magnetic Cu‐MOF‐74 (Fe3O4@SiO2@Cu‐MOF‐74) and a base under O2 atmosphere, yielding the corresponding double benzimidazole‐fused quinazolines and pyrimidines. The catalyst can be recovered using a magnetic bar and reused multiple times without significant loss of catalytic activity. The reaction mechanism likely involves the initial formation of a C−N coupled intermediate through nucleophilic aromatic substitution, followed by oxidative cyclization.

Synthesis of (Z)-Enediynes via Stereoinvertive Nucleophilic Substitution of (E)-Sulfonylethenes with Arylethynide, and Their Aggregation-Induced Optical Properties.

(Z)-Enediynes were successfully synthesized from a trio of terminal ethynes through consecutive three-step reactions: iodosulfonylation of ethyne with I2/PhSO2Na, followed by ethynylations of iodo and sulfonyl moieties of the resulting iodosulfonylethene via Sonogashira-Hagihara coupling and nucleophilic addition-elimination, respectively. The molecular structure of the obtained (Z)-enediyne was fully characterized by X-ray crystal structure analysis, revealing that the nucleophilic substitution of (E)-sulfonylethene with arylethynide underwent a selective stereoinversion. The (Z)-enediynes exhibited photoluminescence in both the solution and solid states (crystals and powders). Ph2N-substituted derivatives showed remarkable solvatofluorochromism, and upon replacing the solvent from toluene to acetonitrile, the emission color changed from blue to yellow.

Synthesis and characterization of two asymmetrical 2-cyclohexylsulfenyl-5-alkylsulfenyl[1,3,4]thiadiazoles and study the impact of substituents on the structural features, thermal behavior, and anti-bacterial activity

Regarding the importance of 1,3,4-thiadiazoles due to versatile biological activity and for investigation of the symmetry impact on thermal behavior and antibacterial activity of 2,5-bisalkylsulfenyl[1,3,4]thiadiazole, two new derivatives viz. 2-cyclohexylsulfenyl-5-cyclopentylsulfenyl[1,3,4]thiadiazole and 2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole, were synthesized through the nucleophilic substitution reaction appropriate alkyl halide with 5-cyclohexyl-3H-[1,3,4]thiadiazole-2-thione in ethanol under reflux conditions. The chemical structure of the products was elucidated by the physical and spectroscopic techniques. After tedious work, the suitable snow-like crystals of 2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole for single-crystal X-ray diffraction analysis could be isolated from a mixed solvent, namely ethanol and water in volume ratio of 9:1. Then, the influence of symmetry and cyclic or non-cyclic aliphatic substituents on the important structure parameters of the 2,5-bisalkylsulfenyl[1,3,4]thiadiazole derivatives were negligible, however, those structure characteristics were different for 5–cyclohexylsulfenyl–3H–[1,3,4]thiadiazole–2–thione, due to its thione structure. TGA/DTA study demonstrated the effect of the symmetry and van der Waals interaction on thermal stability, and the robust influence of the pseudo hydrogen bonding NH with C = S on the melting and crystallization phase transitions was revealed by DSC analysis. The pharmacokinetics, drug-likeness, medicinal chemistry friendliness, and toxicology of three derivatives of bis-alkylsulfenyl[1,3,4]thiadiazole were evaluated by two prediction tools of SwissADME and T.E.S.T tools predicted good pharmacokinetics, drug-likeness, and anti-toxicant properties in developmental toxicity for the bis-alkylsulfenyl[1,3,4]thiadiazoles and 5–cyclohexylsulfenyl–3H–[1,3,4]thiadiazole–2–thione. Finally, the in vitro antibacterial activity of two new 2-cyclohexylsulfenyl-5-cyclopentylsulfenyl[1,3,4]thiadiazole and 2-cyclohexylsulfenyl-5-dodecylsulfenyl[1,3,4]thiadiazole against S. aureus and E. coli, confirmed them as promising anti-bacterial agent. All obtained results proved that the physicochemical, thermal, pharmacokinetic, and biological properties of 2,5-bisalkylsulfenyl[1,3,4]thiadiazoles can be tuned by selecting appropriate substituents.

Nucleophilic Displacement Reactions of Silver-Based Metal-Organic Chalcogenolates.

We report nucleophilic displacement reactions that can increase the dimensionality or coordination number of silver-based metal-organic chalcogenolates (MOChas). MOChas are crystalline ensembles containing one-dimensional (1D) or two-dimensional (2D) inorganic topologies with structures and properties defined by the choice of metal, chalcogen, and ligand. MOChas can be readily prepared from a variety of small-molecule ligands and metals or metal ions. Although MOChas offer ligand diversity, most reported examples use relatively small ligands, typically involving short alkyl chains, aryl rings, or molecular cages. This is because larger, more complex molecules often yield poor product morphologies with indeterminate structures. In this study, we overcame this limitation by employing a ligand exchange strategy whereby a 1D MOCha, silver(I) methyl 2-mercaptobenzoate (2MMB), is used as a silver source for preparing 2D examples. The reaction proceeds generally toward products composed of the stronger nucleophile. We show that the reaction prefers displacing 1D topologies to yield 2D ones and replacing thiolates with selenolates. We performed a study to characterize the mechanism by which organic chalcogenols and dichalcogenides exchange with MOChas. The collected data and product analysis support a proposed mechanism of nucleophilic substitution, explaining how both organic chalcogenols and dichalcogenides can displace ligands in MOChas. This work provides a new synthetic route that will enable the preparation of more elaborate MOChas and heterostructures thereof. This approach enabled the preparation of previously inaccessible oligophenyl MOChas, which were successfully solved via small-molecule serial femtosecond crystallography (smSFX) at the SPring-8 Ångström Compact Free Electron LAser (SACLA) facility.

De(sulfon)amidative Cyclization: The Synthesis of Dibenzolactams and Dibenzosultams for Organic Light Emitting Diode Materials

This study addresses a challenge in organic synthetic chemistry: the direct cleavage of amide bonds, which is typically hampered by the thermodynamic stability of the C(Ar)–C(acyl) bond. Previous methods often rely on “CO” extrusion‐jointing transition metal‐catalyzed process and require activated tertiary amides, limiting their applicability due to incompatibility with reactive functional groups such as halogens. Herein, we report a transition metal‐free approach for the deamidative cyclization of biaryl diamides via a radical process, yielding dibenzolactam derivatives. Along this line, we have developed the desulfonamidative cyclization of biaryl disulfonamides to produce dibenzosultams through direct nucleophilic aromatic substitution, demonstrating high selectivity for unsymmetrical structures. Additionally, unsymmetrical sulfamoyl biaryl amides, containing both amide and sulfonamide functionalities, can selectively undergo desulfonamidative coupling with the amide to form dibenzolactams, which offers a complementary synthetic pathway to unsymmetric dibenzolactams. These protocols exhibit excellent compatibility with reactive functional groups, including halogens, providing an innovative synthetic toolbox for the development of thermally activated delayed fluorescence (TADF) materials used in organic light emitting diodes (OLEDs). DMAC‐PDO, incorporating a dibenzolactam as the acceptor unit, serves as an efficient blue TADF emitter with a maximum external quantum efficiency (EQEmax) of 23.4%.

De(sulfon)amidative Cyclization: The Synthesis of Dibenzolactams and Dibenzosultams for Organic Light Emitting Diode Materials.

This study addresses a challenge in organic synthetic chemistry: the direct cleavage of amide bonds, which is typically hampered by the thermodynamic stability of the C(Ar)-C(acyl) bond. Previous methods often rely on "CO" extrusion-jointing transition metal-catalyzed process and require activated tertiary amides, limiting their applicability due to incompatibility with reactive functional groups such as halogens. Herein, we report a transition metal-free approach for the deamidative cyclization of biaryl diamides via a radical process, yielding dibenzolactam derivatives. Along this line, we have developed the desulfonamidative cyclization of biaryl disulfonamides to produce dibenzosultams through direct nucleophilic aromatic substitution, demonstrating high selectivity for unsymmetrical structures. Additionally, unsymmetrical sulfamoyl biaryl amides, containing both amide and sulfonamide functionalities, can selectively undergo desulfonamidative coupling with the amide to form dibenzolactams, which offers a complementary synthetic pathway to unsymmetric dibenzolactams. These protocols exhibit excellent compatibility with reactive functional groups, including halogens, providing an innovative synthetic toolbox for the development of thermally activated delayed fluorescence (TADF) materials used in organic light emitting diodes (OLEDs). DMAC-PDO, incorporating a dibenzolactam as the acceptor unit, serves as an efficient blue TADF emitter with a maximum external quantum efficiency (EQEmax) of 23.4%.

Nickel‐Catalyzed Reductive Protocol to Access Silacyclobutanes with Unprecedented Functional Group Tolerance

AbstractWhile significant progress has been made in the area of transition metal‐catalyzed ring‐opening and formal cycloaddition reactions of 1,1‐disubstituted silacyclobutanes (SCBs), synthesizing these SCBs—particularly those bearing additional functional groups—continues to present synthetic challenges. In this context, we present a novel Ni‐catalyzed reductive coupling reaction that combines 1‐chloro‐substituted silacyclobutanes with aryl or vinyl halides and pseudohalides, thereby obviating the need for organometallic reagents. This method facilitates the generation of 1,1‐disubstituted silacyclobutanes with a remarkable tolerance for various functional groups. This approach serves as a complementary and more step‐economical alternative to the commonly used yet moisture‐ and air‐sensitive nucleophilic substitution reactions involving Grignard or lithium reagents. Our initial mechanistic studies indicate that this reaction is initiated by oxidative cleavage of the Si−Cl bond in 1‐chlorosilacyclobutanes, which represents a distinct mechanism from the previously documented reductive coupling processes involving carbon electrophiles and chlorosilanes.

Recent Advances in Chlorination: Novel Reagents and Methods from the Last Decade

Chlorinated compounds are vital in organic synthesis, impacting nucleophilic substitutions, β-elimination, and C-H acidity. This review highlights recent advances in (hetero)arene chlorination, focusing on novel reagents and methods developed in the past decade. Traditional electrophilic agents like Cl₂ and PCl₅ have been expanded with new chlorinating agents such as Palau’chlor, as well as electrochemical and photochemical techniques. Biocatalyzed chlorination using FAD-dependent halogenases is also explored. Key trends include green chemistry with eco-friendly chlorine sources like NaCl and HCl. Although nucleophilic chlorination remains rare, electrochemical methods show promising, despite equipment limitations. This review emphasizes significant progress in the last decade towards more sustainable and efficient chlorination strategies.

Deuterated-alkylation reagents based on sulfonium salts as cation and radical sources

Abstract The replacement of C–H bonds with more stable C–D bonds at the α-position of heteroatoms, which is the typical metabolic site for cytochrome P450, is important in drug discovery. Recently, we have developed dn (deuterated)-alkylated sulfonium salts (1a-dn), which were easily prepared by deuteration (H/D exchange reaction) with D2O of the corresponding alkyl diphenylsulfonium salts (1a), as electrophilic dn-alkylating reagents (cation sources). Herein, we newly report an improved preparation method of 1a and one-pot synthesis of dn-alkylated compounds via the deuteration of 1a with D2O and the subsequent nucleophilic substitution under basic conditions. Additionally, dn-alkyl thianthrenium salts (1b-dn) were also found to work as dn-alkylating reagents (cation sources). Furthermore, 1b-dn served as radical sources under photo-induced reaction conditions with Ir photocatalyst, Hantzsch ester, or triphenylamine to obtain various regioselectively deuterium-incorporated alkyl compounds. These dn-alkylating reagents will contribute to advance the drug discovery.