Nucleophilic Aromatic Substitution Research Articles

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.

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%.

Polydimethylsiloxanes - Based Fluorescent Probe for H2S Detection in Living Cells.

The development of fluorescent probes for H2S detection especially in living cells is of great significance due to its fundamental role as signal molecule. A promising scaffold for the development of such probes is polydimethylsiloxanes (PDMS), which is cost-effectiveness, non-toxicity, flexibility, and biocompatibility and easy to post-functionalize. Surprisingly, fluorescent probes for H2S detection based on PDMS have not been investigated. Moreover, 4-nitro - 2,1,3-benzoxadiazole (NBD) derivates provides high fluorescence quantum yield, a large molar absorption coefficient, and sensitivity to environmental changes. Through reasonable design and adjustment of substituents on the NBD group, precise control of its fluorescence properties can be achieved. Herein, a novel H2S fluorescent probe, P-NBD, was designed and synthesized by a one-step aromatic ring nucleophilic substitution of Cl-NBD with a PDMS derivative. Due to the occurrence of the cleavage reaction strategy and the intramolecular charge transfer process, P-NBD can detect H2S via a colorimetric method. The limit of detection is down to 93 nM. P-NBD demonstrated considerable detection capability comparable to other reported types of H2S probes. Moreover, the probe can also be utilized for H2S imaging in HeLa cells. This work provides new insights into the design and synthesis of novel H2S probes while also offering experimental evidence for the application of PDMS in cellular imaging.

Aryl/fluoroaryl-substituted triphenylene discotic liquid crystals: Synthesis, mesomorphism, and photophysical properties

Fluorine aromatic hydrocarbons are ubiquitous optoelectronic functional materials and their efficient synthetic methods are still the subject of rapid, ongoing development. Here, several aryl- and fluoroaryl-substituted triphenylenes (Ar-TP/FAr-TP) were synthesized via either Suzuki-Miyaura cross-coupling or aromatic nucleophilic substitution (SNAr) of perfluoroarenes, respectively, starting indifferently from 2-bromo-3,6,7,10,11-pentakis(hexyloxy)triphenylene (Br-TP). These compounds possess very high thermal stability with initial decomposition temperature over 300 °C, as measured by thermal gravimetric analysis (TGA). Differential scanning calorimetry (DSC), polarized optical microscopy (POM), and small/wide angle X-ray scattering (S/WAXS) revealed that they all self-organize into hexagonal columnar (Colhex) mesophase over broad temperature ranges, occurring at room temperature for some of them, with higher stability than the archetypical 2,3,6,7,10,11-hexakis(hexyloxy)triphenylene parent compound. Under the combined influence of the conjugated π-system and core-side arm distortion, the clearing temperatures and mesophase ranges increase from phenyl- (P-TP), naphthyl- (N-TP), to biphenyl-triphenylene (BP-TP). The number of fluorine atoms on the side fluoroaryl group also impacts the columnar mesomorphism: the more fluorine atoms, the higher the clearing temperatures and the wider the Colhex phase ranges, concomitantly with increasing arene-fluorarene intermolecular interactions. In addition, these compounds show blue-violet photoluminescence in solution: the largest fluorescent absolute quantum yield is measured for BP-TP (45 %), while the smallest is for 7FN-TP (10 %). Perfluoroaryls tend to lower the LUMO, which results in fluorescence red-shift. The arene-perfluoroarene polar-π interactions improve the physical properties of these FAr-TP discotic liquid crystals.

Post-functionalization of Fluorinated Dibenzosulfone-based Conjugated Polymer for Smart 'Turn-off' Sensing of Cu2+ Ions.

Post-functionalization of conjugated polymeric backbone with various N-containing heterocycles through nucleophilic aromatic substitution reaction (SNAr) demonstrates crucial tailoring of their photophysical properties. This study explores an approach of post-polymerization modification of a fluorinated dibenzosulfone-based conjugated polymer aiming to incorporate functional groups having coordinating sites to bind metal ions. The resulting polymers, namely BDT-DBTS-IM, BDT-DBTS-TR, and BDT-DBTS-PY, revealed successful substitution reactions with imidazole, triazole, and pyridine respectively, andshowed significant changes in their absorption and emission properties. Notably, BDT-DBTS-IM demonstrated exceptional performance as a chemosensor, exhibiting a dramatic fluorescence turn-off response specifically to copper ions (Cu2+) with the limit of detection of 26 nM and Stern-Volmer quenching constant (KSV) of 8.2×105 Lmol-1. This high selectivity and sensitivity are attributed to the ability of the imidazole group to form a stable complex with Cu2+, resulting in both static and dynamic quenching efficiently. Our findings underscore the potential of post-polymerization modifications to significantly enhance the functionality of conjugated polymers. The ability of BDT-DBTS-IM to detect trace levels of copper ions with high precision highlights its practical utility in environmental and biological monitoring. This research not only demonstrates an approach for post-polymeric modification through SNAr reaction but also opens new avenues for developing sensors.

Mechanism-Based Regiocontrol in SNAr: A Case Study of Ortho-Selective Etherification with Chloromagnesium Alkoxides.

Although nucleophilic aromatic substitution (SNAr) is routinely employed as a practical alternative to transition-metal-catalyzed cross-coupling, the mechanistic basis for reactivity and regioselectivity remains underexplored and is an active area of research. This article reports a SNAr-based etherification of 2,4-difluoroarylcarboxamides as a model system and shows that the ortho/para regioselectivity spans >500:1 to 1:∼20 simply by varying the reaction conditions via high-throughput experimentation (HTE). An in-depth characterization of the ortho-selective lead conditions is presented, and these insights are used to build a reactivity model that self-consistently accounts for the regioselectivity and reaction scope. This article discusses synthetic implications of condition-dependent magnesium coordination and Schlenk equilibria and demonstrates that consideration of molecular-level stoichiometry and isomerism is an essential prerequisite for rationalizing reactivity and regioselectivity in SNAr.

Controlled Nucleophilic Aromatic Substitution of Hexafluorobenzene Using a Flow Microreactor

Nucleophilic aromatic substitution (SNAr) contributes to creating a variety of useful materials. It is well-known that selective SNAr reactions of perfluorinated aromatics such as hexafluorobenzene with nucleophiles are difficult to achieve using conventional macro batch systems due to the contamination of the di-substituted products. To take advantage of flow microreactor system, we succeeded in the controlled SNAr reactions of hexafluorobenzene with organolithiums employing continuous flow reactors.

Development of Donor-acceptor-type Molecules and Their Application as Analytical Reagents

π-Extended donor-acceptor (D-A)-type molecules, which bear both electron-donor and electron-acceptor substituents on the backbone, exhibit unique optical properties, such as bathochromic shifts in absorption and emission, large Stokes shifts, solvatochromic behavior, and fluorescence quenching in polar solvents. These unique properties are attributed to intramolecular charge transfer (ICT) or twisted intramolecular charge transfer (TICT) in the ground and excited states. This review article introduces three types of D-A-type molecules that are used as detection reagents for (1) methanol, (2) amino acids during solid-phase peptide synthesis (SPPS), and (3) amines present in the biological environment. For methanol detection, D-A-type fluorophores with basic guanidine moieties were developed to differentiate between methanol (MeOH) and ethanol (EtOH) based on the small difference in their pKa values (ΔpKa=0.4). Selective protonation of the guanidine moiety in methanol disrupts the D-A structure, allowing emission in the resultant polar environment. Similarly, an acid-base reaction between the hydrogen chloride (HCl) salts of the D-A-type molecules and amines is applied to detect amines during SPPS. In this method, a colorless solution of an HCl salt of the D-A-type molecule is deprotonated by amines, forming a yellow solution. This is the first reported quantitative and non-destructive colorimetric method for detecting amines. Finally, a turn-on-type amine-labeling reagent was developed for the nucleophilic aromatic substitution (SNAr) reaction. This new reagent enables protein staining of living cells with a large Stokes shift and without solvent-polarity-dependent fluorescence quenching.

Discovery of electrophilic degraders that exploit SNAr chemistry.

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles. In this study, we report the use of chemical moieties that enable nucleophilic aromatic substitution (SNAr) reactions in the rational design of electrophilic protein degraders. Appending an SNAr covalent warhead to several preexisting small molecule inhibitors transformed them into degraders, obviating the need for a defined E3 ligase recruiter. The SNAr covalent warhead is versatile; it can recruit various E3 ligases, including DDB1 and CUL4 associated factor 11 (DCAF11), DDB1 and CUL4 associated factor 16 (DCAF16), and possibly others. The incorporation of an SNAr covalent warhead into the BRD4 inhibitor led to the discovery of degraders with low picomolar degradation potency. Furthermore, we demonstrate the broad applicability of this approach through rational functional switching from kinase inhibitors into potent degraders.

Serendipity as a Driving Force in the Synthesis of Isatins Substituted with Electron-Donating Groups

AbstractAn efficient synthetic procedure for the synthesis of isatins was found after careful analysis of the serendipitous results of the unexpected products obtained by aromatic nucleophilic substitution when it was attempted to introduce 6-fluoroisatins to the classic Pfitzinger reaction. Attentive analysis of these results led to elaborating a methodology for synthesizing electron-enriched isatins, including those with hydroxy-, alkoxy-, alkylthio-, and dialkylamino-substituted aromatic rings. Limitations of the method were established. The reaction conditions were optimized according to the understanding of water’s role. Finally, the classic Pfitzinger reaction procedure was modified to yield the expected 2-substituted 7-fluoroquinoline-4-carboxylic acids.

Amination and hydrodefluorination of aryl fluorides promoted by solvated electrons.

Cross-coupling reactions for constructing C-N bonds represent a pivotal advancement in chemical science. Traditional methodologies, including nucleophilic aromatic substitution (SNAr) and transition metal-catalyzed cross-couplings, have limitations concerning aryl scope, reliance on toxic and costly transition-metal catalysts, and issues related to atom economy and waste generation from ligands and additives. In this work, we introduce a novel method for aminating neutral, electron-rich, and electron-deficient aryl halides, eliminating the need for transition metals. Our approach involves the activation of aryl halides using solvated electrons generated from granulated lithium and sonication. This serves as a sustainable source of reducing power, facilitating the efficient formation of C-N bonds under near ambient conditions. Competitive selectivity studies between halide and ester functionalities were explored. Reaction scope and conducted mechanistic studies support the proposed radical-nucleophilic substitution (SRN1) mechanism for the reaction. Notably, the developed reaction has a highly competitive reductive dehalogenation pathway during the C-N coupling reaction, and this mechanistic divergency was thoroughly explored. This work not only broadens the scope of C-N coupling reactions which typically employs aryl bromides and iodides and rarely aryl fluorides which is also equally abundant, but also introduces a new way to do C-N coupling reactions using solvated electrons.

A near-infrared fluorescent probe with a large Stokes shift for the detection and imaging of biothiols in vitro and in vivo.

In this study, a new near-infrared (NIR) fluorescent turn-on probe featuring a large Stokes shift (198nm) was developed for the detection of biothiols. The probe was based on a dicyanoisophorone derivative serving as the fluorophore and a 2,4-dinitrobenzenesulfonyl (DNBS) group functioning as both a recognition site and a fluorescence quencher. In the absence of biothiols, the fluorescence of the probe was low due to the photoinduced electron transfer (PET) effect between the fluorophore and DNBS. Upon the presence of biothiols, the DNBS group underwent a nucleophilic aromatic substitution reaction with the sulfhydryl group of biothiols, leading to the release of the fluorophore and a notable emission peak at 668nm. This developed probe exhibited exceptional selectivity and sensitivity to biothiols in solution, with an impressive detection limit of 28nM for cysteine (Cys), 22nM for homocysteine (Hcy), and 24nM for glutathione (GSH). Furthermore, the probe demonstrated its applicability by successfully visualizing both endogenous and exogenous biothiols in living systems.

Metal-Free Wet Chemistry for the Fast Gram-Scale Synthesis of γ-Graphyne and its Derivatives.

γ-Graphyne (GY), an emerging carbon allotrope, is envisioned to offer various alluring properties and broad applicability. While significant progress has been made in the synthesis of GY over recent decades, its widespread application hinges on developing efficient, scalable, and accessible synthetic methods for the production of GY and its derivatives. Here we report a facile metal-free nucleophilic crosslinking method using wet chemistry for fast gram-scale production of GY and its derivatives. This synthesis method involves the aromatic nucleophilic substitution reactions between fluoro-(hetero)arenes and alkynyl silanes in the presence of a catalytic amount of tetrabutylammonium fluoride, where the fluoride plays a crucial role in removing protective groups from alkynyl silanes and generating reactive alkynylides. Our comprehensive analysis of the as-prepared GY reveals a layered structure, characterized by the presence of the C(sp)-C(sp2) bond. The synthetic strategy shows remarkable tolerance to various functional groups and enables the preparation of diverse F-/N-rich GY derivatives, using electron-deficient fluoro-substituted (hetero)arenes as precursors. The feasibility of producing GY and derivatives from fluorinated (hetero)arenes through the metal-free, scalable, and cost-effective approach paves the way for broad applications of GY and may inspire the development of new carbon materials.

Dual-Factor-Controlled Dynamic Precursors Enable On-Demand Thermoset Degradation and Recycling.

Thermosets are well known for their advantages such as high stability and chemical resistance. However, developing sustainable thermosets with degradability and recyclability faces several principal challenges, including reconciling the desired characteristics during service with the recycling and reprocessing properties required at the end of life, establishing efficient methods for large-scale synthesis, and aligning with current manufacturing process. Here a general strategy is presented for the on-demand degradation and recycling of thermosets under mild conditions utilizing dynamic precursors with dual-factor-controlled reversibility. Specifically, dynamic triazine crosslinkers are introduced through dynamic nucleophilic aromatic substitution (SNAr) into the precursor polyols used in polyurethane (PU) synthesis. Upon removal of the catalyst and alcohol, the reversibility of SNAr is deactivated, allowing for the use of standard PU polymerization techniques such as injection molding, casting, and foaming. The resulting cyanurate-crosslinked PUs maintain high stability and diverse mechanical properties of traditional crosslinked PUs, yet offer the advantage of easy on-demand depolymerization for recycling by activating the reversibility of SNAr under specific but mild conditions-a combination of base, alcohol, and mild heat. It is envisioned that this approach, involving the pre-installation of dual-factor-controlled dynamic crosslinkers, can be broadly applied to current thermosetting plastic manufacturing processes, introducing enhancedsustainability.

N-heterocyclic carbene-catalyzed nucleophilic aromatic substitution reaction of polyfluoroarenes

Fluorinated asymmetric aryl ketones represent a pivotal class of organic synthesis intermediates, which have garnered widespread application in the realms of organic chemistry, materials science, and drug discovery. Herein, we report a pioneering nucleophilic aromatic substitution (S N Ar) reaction involving aryl aldehydes and polyfluoroarenes, elegantly catalyzed by N-heterocyclic carbene (NHC). This innovative strategy yields bis(hetero)aryl ketone products in yields ranging from moderate to exceptional (40–83%), all achieved under gentle conditions, devoid of both transition metals and directing groups. The versatility of this method is underscored by its compatibility with a broad spectrum of substrates, particularly exhibiting remarkable resilience toward alkoxy functional groups. Notably, we have successfully transformed an array of biologically active molecules, crafting a series of their corresponding derivatives with precision.

Amination of Aminopyridines via η6-Coordination Catalysis.

Pyridine, a widespread aromatic heterocycle, features a sp2-hybridized nitrogen atom that can readily coordinate to metals, leading to distinctive achievements in catalysis. In stark contrast, π-coordination of pyridine and derivatives with transition metals is notably scarce, and the involvement of such activation mode in catalysis remains to be developed. Herein, we present amination reactions of aminopyridines that leverages the reversible π coordination with a ruthenium catalyst as the arenophilic π acid, rather than relying on the conventional κ-N coordination. Specifically, a transient η6-pyridine complex functions as the electrophile in the nucleophilic aromatic substitution with amines, providing a diverse array of products via the cleavage of the pyridyl C-N bond. In addition, this method can be employed to incorporate chiral amines and 15N-labeled amines.

Multi-Substituted Phosphonated and Sulfonated Polymer Materials: Characterization and Blends with Basic Polymers

The growing demand for energy, limited resources, and climate warming call for alternative sustainable energy production. A promising candidate is the proton-exchange membrane fuel cell (PEMFC) using a proton conducting polymer as an electrolyte membrane. The most common proton-exchange membranes are based on sulfonated polymers, such as Nafion®. Since their proton conduction is driven by hydronium ions (H3O+) and hence require water, the operating temperature is limited to 100°C. Unlike in sulfonated polymer materials, the proton conduction in materials with phosphonic acid groups occurs via a hopping process and does not require water.1 This study introduces a highly substituted phosphonated and sulfonated polymer based on poly(pentafluorostyrene), which makes the material adaptable in anhydrous and hydrous operating conditions since the phosphonic acid and sulfonic acid units can conduct cooperatively. The phosphonic acid group is introduced via the nucleophilic aromatic substitution Michaelis-Arbuzov reaction. The Para-Fluoro-Thiol reaction was used to introduce sulfonic acid groups into the polymer backbone. In the past, both reaction steps were well investigated.2,3 The highly substituted polymer material was blended with a basic polymer to circumvent water solubility and investigated according to its proton conductivity, thermal stability, and mechanical properties.(1) Kumar, A. J. Mater. Chem. A 2020, 8 (43), 22632–22636. DOI: 10.1039/d0ta07732a.(2) Atanasov, V.; Oleynikov, A.; Xia, J.; Lyonnard, S.; Kerres, J. Journal of Power Sources 2017, 343, 364–372. DOI: 10.1016/j.jpowsour.2017.01.085.(3) Delaittre, G.; Barner, L. Polym. Chem. 2018, 9 (20), 2679–2684. DOI: 10.1039/c8py00287h.

(Invited) Synthesis and Optical Properties of Circularly Accumulated Carbazole Oligomers

Carbazole oligomers were synthesized to elucidate the physical properties arising from the interaction between circularly accumulated carbazoles. Aromatic nucleophilic substitution reactions were used to synthesize the target compounds, in which carbazoles were substituted for benzene, naphthalene, and anthracene. Structure-property relationships were evaluated by single-crystal structure analysis, theoretical calculations, and optical measurements including ultrafast time-resolved spectroscopy.

Benzisoselenazoles as Selenophenolate Anion Surrogates for the Formation of Carbon-Selenium Bonds via the Selena-Kemp Reaction.

The in situ base-promoted generation of unstable selenophenolate anions from 1,2-benzisoselenazoles via a variant of the Kemp elimination has been developed. 2-Cyano-substituted selenophenolate anions obtained by this methodology were engaged in nucleophilic substitution, aromatic nucleophilic substitution, and Pd-catalyzed cross-coupling reactions to give functionalized arylalkyl and diaryl selenides in moderate to excellent yields.