Aromatic Substitution Mechanism Research Articles

Discovery of a Tunable Heterocyclic Electrophile 4-Chloro-pyrazolopyridine That Defines a Unique Subset of Ligandable Cysteines.

Electrophilic small molecules with novel reactivity are powerful tools that enable activity-based protein profiling and covalent inhibitor discovery. Here, we report a reactive heterocyclic scaffold, 4-chloro-pyrazolopyridine (CPzP) for selective modification of proteins via a nucleophilic aromatic substitution (SNAr) mechanism. Chemoproteomic profiling reveals that CPzPs engage cysteines within functionally diverse protein sites including ribosomal protein S5 (RPS5), inosine monophosphate dehydrogenase 2 (IMPDH2), and heat shock protein 60 (HSP60). Through the optimization of appended recognition elements, we demonstrate the utility of CPzP for covalent inhibition of prolyl endopeptidase (PREP) by targeting a noncatalytic active-site cysteine. This study suggests that the proteome reactivity of CPzPs can be modulated by both electronic and steric features of the ring system, providing a new tunable electrophile for applications in chemoproteomics and covalent inhibitor design.

Regioselective amination of 4-methylene-5,7-dinitroquinazoline: a mechanistic consideration on non-conventional N-H—π interactions between amine and ethylene moiety

ABSTRACT Pi (π) interactions originating from the N-H bond of amine and ethylene moiety have been explored on the mechanism of aromatic nucleophilic substitution (ArSN) of the nitro group of 4-methylene-5,7-dinitroquinazoline with methylamine in the gas phase and solvent media within DFT framework. The free energy profiles confirmed that the amination should take place at peri-position and calculations support the one-step mechanism through a transition state with no intermediate in the reaction route. Stabilisation of peri-transition state by intramolecular weak interaction akin to hydrogen bonding N-H—CH2 = C leads to the regioselective amination at peri-position of 4-methylene-5,7-dinitroquinazoline. The intramolecular hydrogen bond interactions at N-H—CH2 = C in the peri-transition state are strongly supported by a red shift in N-H stretching vibrations in simulated IR spectra and are confirmed by studying energetics of amination of structural/electronic analogues of 4-methylene-5,7-dinitroquinazoline. The present study established that ethylene plays an important role as an efficient H-bond acceptor in fixing the regioselectivity at peri-position in the amination of 4-methylene-5,7-dinitroquinazoline. This is the first-ever report for the exploration of the role of ethylene moiety as a hydrogen bond acceptor in mediating the regioselectivity of organic reactions.

Photo-Induced α-Oxyalkylation of Aryl Chlorides with Ethers and Alcohols through Homolytic Aromatic Substitution

AbstractThe α-oxyalkylation of aryl chlorides with ethers and alcohols using a small amount of a peroxide was found to be induced by photoirradiation. The reaction proceeds through a homolytic aromatic substitution (HAS) mechanism consisting of addition of an α-oxyalkyl radical to an aryl chloride and elimination of the chlorine atom to give the α-oxyalkylation product, where photoirradiation is considered to effect not only the initiation step to facilitate homolysis of a peroxide, but also the propagating radical chain.

Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters

In pursuit of unsymmetrical precursors for the novel series of anthracenyl-isoxazole amide (AIM) antitumor agents, a series of substituted anthracenes were subjected to bromination and re-aromatization in our study, during which we solved four single crystal X-ray diffractometry (Sc-xrd) structures which we report herein. The C-9 nitrile oxide, after its reaction with bromine, was isolated, but when subjected to re-aromatization, it returned to the starting 10-bromo nitrile oxide 1, which did provide an accurate crystal structure, with R = 0.018. The 10-halogenated 3-(9’-anthryl)-isoxazole esters were subjected to bromination and re-aromatization. Surprisingly, the yields obtained in the presence of the isoxazole were reasonably good (62–68% isolated yields), and the major diastereomers allowed for the characterization using Sc-xrd. The penta bromo product 2 showed a trans, trans, cis relationship for the four bromines on the A-ring of the anthracene, and we observed that for the unit cell, the atropisomers displayed a 1:1 ratio at the chiral axis between the isoxazole and anthrancene rings. Similarly, the 10-chloro 3 indicated a ratio of 1:1 at the chiral axis in the crystal structure. A base-induced re-aromatization afforded 3,10-dihalogenated analogues selectively in very good yields (X = Cl, 89%; X = Br 92%), of which the dibromo 4 was characterized using Sc-xrd. The improved yields of the unique diastereomeric bromination products suggested the consideration of a novel electrophilic aromatic substitution mechanism driven by the stereo-electronic environment, imposed by the isoxazole ester substituent. The promise of the application of this chemistry in the future development of AIM antitumor agents is suggested.

Bay-Substitution of Perylene Bisimides with Bidentate Nucleophiles: The Case of Aryloxide Anions.

In this study, we delve into the regioselectivity of nucleophilic reactions involving brominated perylene bisimides (PBIs) and various bidentate aryloxide anions, previously associated with an SRN1 mechanism. We present herein a new perspective, suggesting that a single-electron-transfer aromatic nucleophilic substitution (SeT-SNAr) mechanism is a more plausible scenario. Our study reveals the favorable impact of photostimulation on reaction yields, making our method a convenient approach for accessing O-arylated PBIs.

Fluorinated Benzimidazole-Linked Highly Conjugated Polymer Enabling Covalent Polysulfide Anchoring for Stable Sulfur Batteries.

Sulfur is one of the most abundant and economical elements in the p-block family and highly redox active, potentially utilizable as a charge-storing electrode with high theoretical capacities. However, its inherent good solubility in many electrolytes inhibits its accessibility as an electrode material in typical metal-sulfur batteries. In this work, the synthetically designed fluorinated porous polymer, when treated with elemental sulfur through a well-known nucleophilic aromatic substitution mechanism (SN Ar), allows for the covalent integration of polysulfides into a highly conjugated benzimidazole polymer by replacing the fluorine atoms. Chemically robust benzimidazole linkages allow such harsh post-synthetic treatment and facilitate the electronic activation of the anchored polysulfides for redox reactions under applied potential. The electrode amalgamated with sulfurized polymer mitigates the so-called polysulfide shuttle effect in the lithium-sulfur (Li-S) battery and also enables a reversible, more environmentally friendly, and more economical aluminum-sulfur (Al-S) battery that is configured with mostly p-block elements as cathode, anode, and electrolytes. The improved cycling stabilities and reduction of the overpotential in both cases pave the way for future sustainable energy storage solutions.

Catalytic ipso‐Nitration of Organosilanes Enabled by Electrophilic N‐Nitrosaccharin Reagent

AbstractNitroaromatic compounds represent one of the essential classes of molecules that are widely used as feedstock for the synthesis of intermediates, the preparation of nitro‐derived pharmaceuticals, agrochemicals, and materials on both laboratory and industrial scales. We herein disclose the efficient, mild, and catalytic ipso‐nitration of organotrimethylsilanes, enabled by an electrophilic N‐nitrosaccharin reagent and allows chemoselective nitration under mild reaction conditions, while exhibiting remarkable substrate generality and functional group compatibility. Additionally, the reaction conditions proved to be orthogonal to other common functionalities, allowing programming of molecular complexity via successive transformations or late‐stage nitration. Detailed mechanistic investigation by experimental and computational approaches strongly supported a classical electrophilic aromatic substitution (SEAr) mechanism, which was found to proceed through a highly ordered transition state.

Catalytic ipso-Nitration of Organosilanes Enabled by Electrophilic N-Nitrosaccharin Reagent.

Nitroaromatic compounds represent one of the essential classes of molecules that are widely used as feedstock for the synthesis of intermediates, the preparation of nitro-derived pharmaceuticals, agrochemicals, and materials on both laboratory and industrial scales. We herein disclose the efficient, mild, and catalytic ipso-nitration of organotrimethylsilanes, enabled by an electrophilic N-nitrosaccharin reagent and allows chemoselective nitration under mild reaction conditions, while exhibiting remarkable substrate generality and functional group compatibility. Additionally, the reaction conditions proved to be orthogonal to other common functionalities, allowing programming of molecular complexity via successive transformations or late-stage nitration. Detailed mechanistic investigation by experimental and computational approaches strongly supported a classical electrophilic aromatic substitution (SE Ar) mechanism, which was found to proceed through a highly ordered transition state.

Lewis acid/acetic acid-catalysed electrophilic amidation of simple arenes with O-acetyl acetohydroxamic acid

Electrophilic arene CH amination constitutes an intrinsically more atom- and step-economical pathway towards arylamines than CX → CN methods. However, most literature examples are restricted to arenes with extensive directing groups (DG) and/or nitrogen coupling partners with large leaving groups (LG). Moreover, only few cases of EAs using cheap metals (e.g., Fe) have been reported. Herein, we demonstrate the catalytic activity of various Lewis acids in the electrophilic amidation of simple arenes with O-acetyl acetohydroxamic acid in acetic acid. With 5 mol% FeIII(citrate)·H2O, up to 27 % yield was achieved, whereas 5 mol% BiCl3 gave up to 31 % yield. Instability of the amidation agent and product inhibition were identified as the yield-limiting factors. The observed regioselectivity, as well as kinetic and spectroscopic data suggest an electrophilic aromatic substitution mechanism, in which acetic acid and the Lewis acid generate a highly electrophilic species from AcNHOAc.

A NIR fluorescent probe for imaging thiophenol in the living system and revealing thiophenol-induced oxidative stress

Thiophenol (PhSH) is an important raw material for organic synthesis, while its high toxicity to organisms makes it an environmental pollutant. Therefore, it is crucial to accurately detect PhSH and explore its metabolic process in the living system. Herein, a near-infrared (NIR) fluorescent probe TEM-FB was developed for sensing PhSH with a turn-on fluorescent signal at 719 nm and a large Stokes shift (198 nm) based on generating the intramolecular charge transfer (ICT) process. TEM-FB shows high specificity and significant sensitivity towards PhSH (detection limit: 10 nmol/L) via the aromatic nucleophilic substitution mechanism. Furthermore, it was successfully applied to image PhSH in multiple cell lines and in zebrafish. Notably, we revealed the oxidative stress process caused by PhSH and demonstrated that the hydrogen peroxide (H2O2) in cells would alleviate the poisonousness from exogenous PhSH for the first time. This work provides a promising bioimaging tool for monitoring PhSH in living systems and visualizing the process of oxidative stress induced by PhSH.

Evidence of a Wheland Intermediate in Carboxylate-Assisted C(sp2)−H Activation by Pd(IV) Active Catalyst Species Studied via DFT Calculations

Evidence of a Wheland intermediate in carboxylate-assisted C−H activation was found using DFT calculations when the Pd(IV) catalyst species was postulated as the active catalyst species (ACS). In order to delineate the reaction mechanism of Pd-catalyzed bisarylation of 3-alkylbenzofuran, five hypothetical catalyst species, [Pd(OAc)(PMe3)(Ph)] (I), [Pd(OAc)2] (II), [Pd(OAc)2(PMe3)] (III), [Pd(OAc)2(Ph)]+ (IV) and [Pd(OAc)2(PMe3)(Ph)]+ (V) were tested as potential ACS candidates. The catalyst species I, previously reported as an ACS in the context of ambiphilic metal−ligand assistance or a concerted metalation-deprotonation mechanism, was unsuccessful, with maximum activation barriers (ΔG‡max) for the C(sp2)−H and C(sp3)−H activations of 33.3 and 51.4 kcal/mol, respectively. The ΔG‡max values for the C(sp2)−H and C(sp3)−H activations of II−V were 23.8/28.7, 32.0/49.6, 10.9/10.9, and 36.0/36.0 kcal/mol, respectively, indicating that ACS is likely IV. This catalyst species forms an intermediate state (IV_1) before proceeding to the transition state (IV_TS1,2) for C(sp2)−H activation, in which C(2) atom of 3-methylbenzofuran has a substantial σ-character. The degree of σ-character of the IV_1 state was further evaluated quantitatively in terms of geometric parameters, partial charge distribution, and activation strain analysis. The analysis results support the existence of a Wheland intermediate, which has long been recognized as the manifestation of the electrophilic aromatic substitution mechanism yet never been identified computationally.

Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase

C-linked glycosylation is essential for the trafficking, folding and function of secretory and transmembrane proteins involved in cellular communication processes. The tryptophan C-mannosyltransferase (CMT) enzymes that install the modification attach a mannose to the first tryptophan of WxxW/C sequons in nascent polypeptide chains by an unknown mechanism. Here, we report cryogenic-electron microscopy structures of Caenorhabditiselegans CMT in four key states: apo, acceptor peptide-bound, donor-substrate analog-bound and as a trapped ternary complex with both peptide and a donor-substrate mimic bound. The structures indicate how the C-mannosylation sequon is recognized by this CMT and its paralogs, and how sequon binding triggers conformational activation of the donor substrate: a process relevant to all glycosyltransferase C superfamily enzymes. Our structural data further indicate that the CMTs adopt an unprecedented electrophilic aromatic substitution mechanism to enable the C-glycosylation of proteins. These results afford opportunities for understanding human disease and therapeutic targeting of specific CMT paralogs.

Bio-Inspired Deaminative Hydroxylation of Aminoheterocycles and Electron-Deficient Anilines.

Among the tools available to chemists for drug design of bioactive compounds, the bioisosteric replacement of atoms or groups of atoms is the cornerstone of modern strategies. Despite the undeniable interest in amino-to-hydroxyl interchange, enzymatic deaminative hydroxylation remains unmatched. Herein, we report a user friendly and safe procedure to selectively convert aminoheterocycles to their hydroxylated analogues by means of a simple pyrylium tetrafluoroborate salt. The hydroxylation step relies on a Lossen-type rearrangement under mild conditions thus avoiding the use of strong hydroxide bases. In addition to biorelevant heterocycles, the deaminative hydroxylation of electron-deficient anilines was also demonstrated. Finally, mechanistic experiments allowed the identification of the key intermediates, thus unveiling a rather unusual mechanism for this formal aromatic substitution.

Bio‐Inspired Deaminative Hydroxylation of Aminoheterocycles and Electron‐Deficient Anilines

AbstractAmong the tools available to chemists for drug design of bioactive compounds, the bioisosteric replacement of atoms or groups of atoms is the cornerstone of modern strategies. Despite the undeniable interest in amino‐to‐hydroxyl interchange, enzymatic deaminative hydroxylation remains unmatched. Herein, we report a user friendly and safe procedure to selectively convert aminoheterocycles to their hydroxylated analogues by means of a simple pyrylium tetrafluoroborate salt. The hydroxylation step relies on a Lossen‐type rearrangement under mild conditions thus avoiding the use of strong hydroxide bases. In addition to biorelevant heterocycles, the deaminative hydroxylation of electron‐deficient anilines was also demonstrated. Finally, mechanistic experiments allowed the identification of the key intermediates, thus unveiling a rather unusual mechanism for this formal aromatic substitution.

Hydride Relay Exchange Mechanism for the Heterocyclic C-H Arylation of Benzofuran and Benzothiophene Catalyzed by Pd Complexes.

The mechanism and regioselectivity of the heterocyclic C-H arylation of benzofuran and benzothiophene catalyzed by Pd(OAc)2 complexes were investigated using the density functional theory (DFT) method. The Pd(0)L2(PhI) complex (L = HOAc) is proposed to be the catalytic species. Compared to the traditional Heck-type mechanism, concerted metalation-deprotonation (CMD) mechanism, and electrophilic aromatic substitution (SEAr) mechanism for the C-H arylation, a new hydride relay exchange mechanism was proposed for the benzoheterocyclic C-H arylation catalyzed by Pd complexes, which consists of two redox processes between Pd(II) and Pd(0) species to complete the regioselective C-H activation. The calculated results indicate that the reaction along the hydride relay exchange mechanism is more favorable than those along other mechanisms, including the traditional Heck-type mechanism and the base-assisted anti-H elimination mechanism. This agrees well with the experimental results. Meanwhile, the origin for the regioselective C-H arylation was unveiled in which the α-C-H arylation products are major for the heterocyclic C-H arylation of benzofuran, but the β-C-H arylation products are major for that of benzothiophene. This study might provide a deep mechanistic understanding on the regioselective C-H activation and arylation of benzoheterocycle compounds catalyzed by transition-metal complexes.

A profound change from the classic mechanism of electrophilic aromatic substitution in the gas phase to a novel mechanism, including the hydride transfer in the presence of Cucurilbit[6] uril (DFT prediction)

The DFT B3LYP/6–311+G* calculations were carried out for the reactions ArH / CBr3+Al2Br7− (ArH = PhH, PhNH2, PhNMe2) (I) and ArH / CBr3+Al2Br7−/СО (II) in a gas phase. The same reactions in the presence of cucurbit[6]uril (CB6), were calculated by the DFT B3LYP/6–31G* basis set. The calculations show that the classical mechanism of electrophilic aromatic substitution (EAS) in the gas phase changes abruptly when the reactions are carried out in CB6. Unlike the classical mechanism involving the attack of electrophile on the arene C atom with the formation of the tetrahedral cationic intermediate followed by proton substitution by electrophile, in CB6, the cation attacks the arene H atom resulting in high barrier H / Br exchange (reaction I) or low-barrier carbonylation reaction (reaction II) as the only channel in each case.

Regioselective Transfer Hydrogenative Defluorination of Polyfluoroarenes Catalyzed by Bifunctional Azairidacycle

The catalytic hydrodefluorination (HDF) with a bifunctional azairidacycle using HCOOK was examined for cyano- and chloro-substituted fluoroarenes, including penta- and tetrafluorobenzonitriles, tetrafluoroterephthalonitrile, tetrafluorophthalonitrile, 3-chloro-2,4,5,6-tetrafluoropyridine, and 4-cyano-2,3,5,6-tetrafluoropyridine. The reaction was performed in the presence of a controlled amount of HCOOK with a substrate/catalyst ratio (S/C) of 100 in a 1:1 mixture of 1,2-dimethoxyethane (DME) and H2O at an ambient temperature of 30 °C to obtain partially fluorinated compounds with satisfactory regioselectivities. The C–F bond cleavage proceeded favorably at the para position of substituents other than fluorine, which is in consonance with the nucleophilic aromatic substitution mechanism. In the HDF of tetrafluoroterephthalonitrile and 4-cyano-2,3,5,6-tetrafluoropyridine, which do not contain a fluorine atom at the para position of the cyano group, the double defluorination occurred solely at the 2- and 5-positions, as confirmed by X-ray crystallography. The HDF of 3-chloro-2,4,5,6-tetrafluoropyridine gave preference to the C–F bond cleavage over the C–Cl bond cleavage, unlike the dehalogenation pathway via electron-transfer radical anion fragmentation. In addition, new azairidacycles with an electron-donating methoxy substituent on the C–N chelating ligand were synthesized and served as a catalyst precursor (0.2 mol%) for the transfer hydrogenative defluorination of pentafluoropyridine, leading to 2,3,5,6-tetrafluoropyridine with up to a turnover number (TON) of 418.

Diazaphospholene-Catalyzed Hydrodefluorination of Polyfluoroarenes with Phenylsilane via Concerted Nucleophilic Aromatic Substitution.

The metal-free catalytic C-F bond activation of polyfluoroarenes was achieved with diazaphospholene as the catalyst and phenylsilane as the terminal reductant. Density functional theory calculations suggested a concerted nucleophilic aromatic substitution mechanism.

Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2.

Molecular modeling tools were applied to design a potential covalent inhibitor of the main protease (Mpro) of the SARS-CoV-2 virus and to investigate its interaction with the enzyme. The compound includes a benzoisothiazolone (BZT) moiety of antimalarial drugs and a 5-fluoro-6-nitropyrimidine-2,4(1.H,3H)-dione (FNP) moiety mimicking motifs of inhibitors of other cysteine proteases. The BZT moiety provides a fair binding of the ligand on the protein surface, whereas the warhead FNP is responsible for efficient nucleophilic aromatic substitution reaction with the catalytic cysteine residue in the Mpro active site, leading to a stable covalent adduct. According to supercomputer calculations of the reaction energy profile using the quantum mechanics/molecular mechanics method, the energy of the covalent adduct is 21 kcal mol−1 below the energy of the reactants, while the highest barrier along the reaction pathway is 9 kcal mol−1. These estimates indicate that the reaction can proceed efficiently and can block the Mpro enzyme. The computed structures along the reaction path illustrate the nucleophilic aromatic substitution (SNAr) mechanism in enzymes. The results of this study are important for the choice of potential drugs blocking the development of coronavirus infection.

Synthesis, characteristic fragmentation patterns, and antibacterial activity of new azo compounds from the coupling reaction of diazobenzothiazole ions and acetaminophen

Abstract In this study, a series of azobenzothiazole dyes 4 were synthesized via diazotization of substituted benzothiazole derivatives followed by azo coupling with acetaminophen. The chemical structures of all synthesized compounds were confirmed using analytical data and spectroscopic techniques, including UV-visible, IR, mass spectra, and 1H- and 13C-NMR. The in situ formed diazobenzothiazole ions regiospecifically react with acetaminophen derivatives in the Hollemann-guided electrophilic aromatic substitution mechanism. The regio-orientations were established, on the one hand, by a rigorous interpretation of 1H-NMR spectra and, on the other hand, by the characteristic fragmentation patterns observed on the electrospray mass spectra. In the cases of 4a and 4b, multisubstitutions occurred. The antimicrobial activity of compound 4, along with all the starting materials, was investigated on Pseudomonas aeruginosa PA01, Staphylococcus aureus 18, Escherichia coli 64R, and S. aureus ATCC 25923. The results showed that this skeletal framework exhibited marked potency as antibacterial agents. The most active antibacterial agent against both targeted organisms was compound 4a′.