Nucleophilic Aromatic Substitution Research Articles

Complex‐mediated nucleophilic aromatic substitution with aryl nitriles to realize intramolecular flapping‐restricted D‐A AIEgens for bioimaging

AbstractDonor‐acceptor (D‐A) compounds are particularly important in optoelectronic and biological applications. However, they are normally synthesized in the presence of transition metal catalysts. Herein, we report a metal‐free method by a complex‐mediated nucleophilic aromatic substitution of aryl nitriles with amines. The method can lead to rich D‐A type aggregation‐induced emission luminogens (AIEgens) with tunable properties. They emit from deep‐blue to yellow‐green and possess high photoluminescence quantum yields up to 70.5% in the aggregate state. Interestingly, the suppression of intramolecular flapping is proved to play an indispensable role in the AIE behavior, which is different from the mechanism met in other AIEgens. Moreover, the biocompatible AIEgens possess specific staining of lipid droplets in HeLa cells and the superiority of identifying fatty liver over traditional Oil Red O staining is exhibited.

Synthesis of Regular Ladder-Type Fluorenylidene-Xanthene Oligomers via Nucleophilic Aromatic Substitution Reaction.

Fluorenylidene-xanthene and related polycyclic systems are typical examples of bistricyclic aromatic enes (BAEs); however, polycyclic systems of fluorenylidene-xanthene are relatively scarce. Here we synthesized a series of novel ladder-type polycyclic systems containing fluorenylidene-xanthene units, differing from the classic Barton's two-fold extrusion reaction. In the new synthetic scheme, the very popular Suzuki reaction was first used to couple the corresponding precursors, then a catalyst-free nucleophilic aromatic substitution reaction between Ar-F and Ar-OH groups in the backbone afforded ladder-type O-heteroarenes. Moreover, the new synthetic strategy is also suitable for the synthesis of other heterocyclic and polycyclic aromatic hydrocarbons. Some of these products showed reversible mechanochromism properties.

Synthesis of Thieno[3,2-b]thiophenes from 2,5-Dicarbonyl 3-Nitrothiophenes via Nucleophilic Aromatic Substitution of the Nitro Group with Thiolates

Synthesis of Thieno[3,2-b]thiophenes from 2,5-Dicarbonyl 3-Nitrothiophenes via Nucleophilic Aromatic Substitution of the Nitro Group with Thiolates

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, and showed 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.

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.

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.

Novel s-triazine derivatives as potential anticancer agents: Synthesis, DFT, DNA binding, molecular docking, MD simulation and in silico ADMET profiling

The ongoing challenge of cancer in modern medicine highlights the urgent need for targeted therapeutic strategies, particularly against the EGFR/PI3K/AKT/mTOR signalling pathways, which are pivotal in tumorigenesis. This study presents the design, synthesis, characterization, DNA binding studies and computational evaluation of a novel series of trisubstituted s-triazine derivatives 3a–n as potential anticancer agents. The synthetic methodology utilized the reaction of various oxygen-containing nucleophiles with cyanuric chloride via nucleophilic aromatic substitution, yielding the corresponding target products with high yield and purity. Density Functional Theory (DFT) calculations utilizing the B3LYP level provided insights into the electronic properties of the compounds, with derivatives 3f, 3n, and 3l displaying the lowest energy gaps and highest electrophilicity indices, indicative of their enhanced reactivity. DNA binding results from UV–Vis absorption spectroscopy confirmed the groove mode of binding for the most potent compound 3f with the binding constant (Kb) value of 6.75 × 104 M−1. Molecular docking studies against DNA (PDB ID: 3EY0) and EGFR (PDB ID: 6V6O) revealed strong binding affinities, with compound 3f (R1= ethoxy, R2= 3-CF3) exhibiting a notable binding energy of -8.9 kcal/mol and −9.1 kcal/mol respectively. Additionally, these compounds showed significant binding interactions with PI3K (PDB ID: 5HJB) and mTOR (PDB ID: 4JSV), suggesting their potential as dual inhibitors of the PI3K/AKT/mTOR pathway. The drug-likeness and ADMET profiles further support the therapeutic promise of compound 3f bearing a 3-trifluoromethyl substituent.

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.

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

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.

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.

Transition-Metal Free 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 which supported 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.