Electron-deficient Ring Research Articles

Fluorination/Dearomatization of C6F5 Groups: An FLP Route to an Electrophilic Borane and Non-Coordinating Anions.

B(C6F5)3 and the corresponding anion [B(C6F5)4]- are ubiquitous in main group and transition metal chemistry. Known derivatives are generally limited to the incorporation of electron donating substituents. Herein we describe electrophilic fluorination and dearomatization of such species using XeF2 in the presence of BF3 or Lewis acidic cations. In this fashion the anions [HB(C6F5)3]-, [B(C6F5)4]- and [(C6F5)3BC≡NB(C6F5)3]-, are converted to [FB(C6F7)3]-, [B(C6F7)4]-, and [(C6F7)3BC≡NB(C6F7)3]-, respectively. Similarly, the borane adducts (L)B(C6F7)3 (L=MeCN, OPEt3) are produced. These rare examples of electrophilic attack of electron deficient rings proceed as [XeF][BF4] acts as a frustrated Lewis pair effecting fluorination and dearomatization of C6F5 rings.

New Insights into the Opioid Analgesic Profile of cis-(-)-N-Normetazocine-derived Ligands.

In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. To do that, the phenyl ring in the N-substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)-cis-N-normetazocine skeleton. In radioligand binding assays, compounds 3 and 7 were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (Ki = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound 3 showed an antagonist effect against DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound 7 produced naloxone reversible effect at MOR. Moreover, compound 7, as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.

Synthesis and Antitrypanosomal and Mechanistic Studies of a Series of 2-Arylquinazolin-4-hydrazines: A Hydrazine Moiety as a Selective, Safe, and Specific Pharmacophore to Design Antitrypanosomal Agents Targeting NO Release.

Nitric oxide (NO) represents a valuable target to design antitrypanosomal agents by its high toxicity against trypanosomatids and minimal side effects on host macrophages. The progress of NO-donors as antitrypanosomal has been restricted by the high toxicity of their agents, which usually is based on NO-heterocycles and metallic NO-complexes. Herein, we carried out the design of a new class of NO-donors based on the susceptibility of the hydrazine moiety connected to an electron-deficient ring to be reduced to the amine moiety with release of NO. Then, a series of novel 2-arylquinazolin-4-hydrazine, with the potential ability to disrupt the parasite folate metabolism, were synthesized. Their in vitro evaluation against Leishmania and Trypanosoma cruzi parasites and mechanistic aspects were investigated. The compounds displayed significant leishmanicidal activity, identifying three potential candidates, that is, 3b, 3c, and 3f, for further assays by their good antiamastigote activities against Leishmania braziliensis, low toxicity, non-mutagenicity, and good ADME profile. Against T. cruzi parasites, derivatives 3b, 3c, and 3e displayed interesting levels of activities and selectivities. Mechanistic studies revealed that the 2-arylquinazolin-4-hydrazines act as either antifolate or NO-donor agents. NMR, fluorescence, and theoretical studies supported the fact that the quinazolin-hydrazine decomposed easily in an oxidative environment via cleavage of the N-N bond to release the corresponding heterocyclic-amine and NO. Generation of NO from axenic parasites was confirmed by the Griess test. All the evidence showed the potential of hydrazine connected to the electron-deficient ring to design effective and safe NO-donors against trypanosomatids.

A Fast and Precise Synthetic Tool for the Fabrication of Ion Conducting Polymers

The rapidly growing fields of renewable energy technologies and future mobility demands a big step forward in storing the generated energy. Here, rechargeable redox-flow batteries (RFB) can serve as efficient and flexible storage device. The crucial element of the batteries are the ion conductive membranes separating the two electrolyte solutions. These membranes can either be anion- or cation-conductive. The backbone of already applied membrane polymers can vary from aromatic to fluorinated alkyl chains. However, the integration of ion conducting groups into a polymer chain can be challenging in multiple ways. An additional functional group can alter the polymer properties as it could lose its mechanical stability or processability. Another synthetic approach is originating from an already functionalized precursor. Polymerization of the modified precursors can lead to an undesired (low) molecular weight or high polydispersity index (PDI). In this study we report an extremely fast postfunctionalization method giving access to a broad library of ion exchange polymers based on polypentafluorostyrene (PPFS) within few minutes of reaction time. We chose postfunctionalization as the chain length and PDI can be maintained after modification. In this context, the pentafluorophenyl group of the polymer is important as it serves as platform for versatile functional polymers. The strongly electron-deficient ring in combination with the fluorine atom in para-position (4-F) makes fluoride to an excellent leaving group. This enables precise polymer modification with high yields, low synthetic effort and short reaction times. The functionalization could already be demonstrated for the introduction of proton conducting groups, such as sulfonic acid and phosphonic acid.1,2 Yet, membranes of pristine phosphonated or sulfonated PPFS tend to be brittle. Blended with a polybenzimidazole (PBI) they perform extremely good in vanadium redox flow batteries.3 These experiments served as starting points for design of our novel macromolecules in ion exchange membranes for fuel cells and redox-flow batteries. By introducing more flexible side chains by substitution of fluorine the mechanical ductility of the polymer increases. A broad variety of alkyl side chains could successfully be integrated into a phosphonated polymer. A library of varying phosphonic acid to alkyl chain ratios was investigated. Also the mechanical stability was tested with respect to the chain length. As the reaction is accurate with an NMR yield of >99% the amount of alkyl chain can be tuned precisely. Selected polymers were tested as membranes to prove their proton conductivity. Besides alkyl groups other functional groups could be successfully added to the broad library based on PPFS. With this type of reaction, perfluorinated, partially fluorinated or nonfluorinated alkyls, sulfonic acids and amines can be added to PPFS in an instantaneous reaction. In combination with the high thermal and chemical stability of PPFS this method provides an easy access to change the mechanical properties of desired polymers in a large scale and precise manner, paving the way to more cost-efficient materials.References(1) Atanasov, V.; Bürger, M.; Lyonnard, S.; Porcar, L.; Kerres, J. Solid State Ionics 2013, 252, 75–83. DOI: 10.1016/j.ssi.2013.06.010.(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) Bülbül, E.; Atanasov, V.; Mehlhorn, M.; Bürger, M.; Chromik, A.; Häring, T.; Kerres, J. Journal of Membrane Science 2019, 570-571, 194–203. DOI: 10.1016/j.memsci.2018.10.027.

Site-selective and metal-free C\u2013H nitration of biologically relevant N-heterocycles

The site-selective and metal-free C–H nitration reaction of quinoxalinones and pyrazinones as biologically important N-heterocycles with t-butyl nitrite is described. A wide range of quinoxalinones were efficiently applied in this transformation, providing C7-nitrated quinoxalinones without undergoing C3-nitration. From the view of mechanistic point, the radical addition reaction exclusively occurred at the electron-rich aromatic region beyond electron-deficient N-heterocycle ring. This is a first report on the C7–H functionalization of quinoxalinones under metal-free conditions. In contrast, the nitration reaction readily takes place at the C3-position of pyrazinones. This transformation is characterized by the scale-up compatibility, mild reaction conditions, and excellent functional group tolerance. The applicability of the developed method is showcased by the selective reduction of NO2 functionality on the C7-nitrated quinoxalinone product, providing aniline derivatives. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

Crystal Structure and DFT Study of N-(6-(Diphenylamino)Pyridin-2-Yl)-N-Phenylacetamide

The title compound N-(6-(diphenylamino)pyridin-2-yl)-N-phenylacetamide (1) crystallizes in the monoclinic crystal system in the space group P21/n with unit cell parameters a = 9.571(7) A, b = 9.333(6) A, c = 22.431(16) A, β = 100.669(10)°, V = 1969(2) A3, and Z = 4. The structures of amine and amide units are planar. Dihedral angles of a pyridine ring with the amine and amide planes are 20.19(11)° and 37.21(8)°, respectively, indicating that an electron-rich diphenylamino group makes better conjugation with an electron-deficient pyridine ring. The oxygen atom of the amide group forms an intramolecular hydrogen bond with a hydrogen atom of the pyridine ring.

Crystal structure and DFT study of N-(6-(diphenylamino)pyridin-2-yl)-N-phenylacetamide

The title compound N-(6-(diphenylamino)pyridin-2-yl)-N-phenylacetamide (1) crystallizes in the monoclinic crystal system in the space group P21/n with unit cell parameters a = 9.571(7), b = 9.333(6), c = 22.431(16) Å, β = 100.669(10)°, V = 1969(2) Å3, and Z = 4. The structures of amine and amide units are planar. Dihedral angles of a pyridine ring with the amine and amide planes are 20.19(11) and 37.21(8)°, respectively, indicating that an electron-rich diphenylamino group makes better conjugation with an electron-deficient pyridine ring. The oxygen atom of the amide group forms an intramolecular hydrogen bond with a hydrogen atom of the pyridine ring.

Tailoring the benzotriazole (BTZ) auxiliary acceptor in a D-A′-π-A type sensitizer for high performance dye-sensitized solar cells (DSSCs)

Molecular engineering toward decreasing the band gap and thus extending the absorption spectrum of benzotriazole-based dye is a challenge. Herein, the benzotriazole structure is finely tuned by fusing another electron deficient ring to the benzo unit leading to a series of benzotriazole-based electron-withdrawing heterocyclic rings including benzobitriazole, benzotriazolequinoxaline and benzotriazolethiadiazole. These together with benzotriazole are incorporated into the π-bridge, respectively, as an auxiliary acceptor between the triphenylamine donor and the cyanoacrylic acid anchoring group for the construction of donor-auxiliary acceptor-π-acceptor type sensitizers (LC-2, LC-3, LC-4 and LC-5). The benzobitriazole, benzotriazolequinoxaline and benzotriazolethiadiazole units show greatly increased electron-withdrawing capability and the corresponding sensitizers (LC-3, LC-4 and LC-5) exhibit broadened spectral response range compared to the reference benzotriazole-based dye LC-2 due to the decreased energy gap. Thus, the LC-3 and LC-4 cells exhibit significantly enhanced photocurrent density (Jsc) values due to the greater light-harvesting abilities compared to LC-2. However, the electrochemical impedance analysis suggests the electron lifetime and charge recombination resistance are decreased due to the introduction of benzobitriazole, benzotriazolequinoxaline and benzotriazolethiadiazole, resulting in a slight loss of open-circuit voltage (Voc). The findings provide a guidance for the future molecular design of highly efficient organic sensitizers for use in dye-sensitized solar cells.

Pyridinium-Functionalized Pyromellitic Diimides with Stabilized Radical Anion States.

In this work, we report the stabilization of the reduced states of pyromellitic diimide by charge-balancing the imide radical anions with cationic pyridinium groups attached to the aromatic core. This structural modification is confirmed by single-crystal X-ray diffraction analysis. Characterization by (spectro)electrochemical experiments and computations reveal that the addition of cationic groups to an already electron-deficient ring system results in up to +0.57 V shifts in reduction potentials, largely as a consequence of charge screening and lowest unoccupied molecular orbital-lowering effects. This formal charge-balancing approach to stabilizing the reduced states of electron-deficient pyromellitic diimides will facilitate their incorporation into spin-based optoelectronic materials and devices.

Through-Space Activation Can Override Substituent Effects in Electrophilic Aromatic Substitution.

Electrophilic aromatic substitution (EAS) represents one of the most important classes of reactions in all of chemistry. One of the "iron laws" of EAS is that an electron-rich aromatic ring will react more rapidly than an electron-poor ring with suitable electrophiles. In this report, we present unique examples of electron-deficient arenes instead undergoing preferential substitution in intramolecular competition with more electron-rich rings. These results were made possible by exploiting the heretofore unknown propensity of a hydrogen-bonding OH-arene interaction to switch to the alternative HO-arene interaction in order to provide activation. In an extreme case, this through-space HO-arene activation is demonstrated to overcome the deactivating effect of a trifluoromethyl substituent, making an otherwise highly electron-deficient ring the site of exclusive reactivity in competition experiments. Additionally, the HO-arene activation promotes tetrabromination of an increasingly more electron-deficient arene before the unactivated "control" ring undergoes monobromination. It is our hope that these results will shed light on biological interactions as well as provide new strategies for the electrophilic substitution of aromatic rings.

A new fluorogenic sensing platform for salicylic acid derivatives based on π-π and NH-π interactions between electron-deficient and electron-rich aromatics

A novel simple fluorescent probe was designed for the recognition of electron-rich salicylic acid derivatives (SAs). The imidazole-appended aminomethyl perylene probe 1 selectively differentiated between electron-rich amino-SAs and electron-deficient nitro-SAs in EtOH, exhibiting the highest selectivity and sensitivity toward 5-aminosalicylic acid (5-ASA) and showing strong 1:1 binding (Ka=1.37×107M−1). This high selectivity and sensitivity resulted from the synergistic multiple hydrogen bonding interactions of secondary amine and imidazole units and π-π interactions between electron-rich and electron-deficient rings, along with the unusual NH-π interactions between 5-ASA and the perylene moiety of 1. The limit of detection (LOD) for 5-ASA in EtOH was 0.012ppb.

ChemInform Abstract: Novel Access to Carbonyl and Acetylated Compounds: The Role of the Tetra‐n‐butylammonium Bromide/Sodium Nitrite Catalyst.

A novel aerobic oxidation of alcohols without the use of any oxidants was developed. An equimolar catalytic mixture of tetra-n-butylammonium bromide and sodium nitrite catalyzes the aerobic selective oxidation of benzylic alcohols under oxidant-free, base-free and metal-free conditions. The mild reaction conditions allow oxidation of a wide range of benzylic alcohols, chemo-selectively to their carbonyl compounds (68–93% isolated yields). More importantly, high selectivity among different kinds of alcohols (aromatic vs. aliphatic alcohols, primary vs. secondary alcohols as well as alcohols having neutral rings vs. electron-deficient rings) is available by this approach. The method surprisingly switched over to be an efficient acetylation approach in the case of aliphatic alcohols without the use of any transition metal, phosphorous or other toxic reagents or any need for using toxic acyl halides, sulfonyl halides, anhydrides, etc. by the use of only acetic acid as a reagent.

Reactions of Nucleophiles with Nitroarenes: Multifacial and Versatile Electrophiles

In this overview, it is shown that there are many initial reactions between nitroarenes and nucleophiles: addition to the electron-deficient ring at positions occupied by halogen and hydrogen atoms, addition to the nitro group, single-electron transfer (SET), and other types of initial reactions. The resulting intermediates react further in a variety of ways to form products of nucleophilic substitution of a halogen atom (SN Ar), a hydrogen atom (SN ArH), and others. Many variants of these processes are briefly discussed, particularly in relation of rates of the initial reactions and further transformations.

The smart precursors of energetic–energetic cocrystals from eutectic precursors

Abstract The selected 18 energetic compounds were theoretically investigated by using the density functional theory (DFT) quantum mechanical code, DMol 3 , and the Hansen solubility parameters (HSPs) analyses. The results showed that 4-nitrotoluene, 4-nitrophenol, N , N ′-dimethyl- N , N ′-diphenylurea and N , N ′-diethyl- N , N ′-diphenylurea contain relatively electron-rich aromatic rings. Four satisfactory energetic precursors with electron-rich rings were quickly and effectively found by electrostatic potential (ESP) surfaces and HSPs analyses. The results also indicated that the absolute value of the lowest unoccupied molecular orbital (LUMO) of the energetic precursors with electron-rich rings often was less than 3.00 eV, and the absolute value of LUMO of the energetic precursors with electron deficient rings was often more than 3.00 eV. Additionally, we found that with at least two eutectic points was a prerequisite for two precursors to form a cocrystal.

Cover Picture: On the Importance of Anion–π Interactions in the Mechanism of Sulfide:Quinone Oxidoreductase (Chem. Asian J. 11/2013)

The anion–π interaction is a well-recognized noncovalent force that is established between electron-deficient rings and anions. In the Communication by Antonio Frontera and co-workers on page 2708 ff., the relevance of this noncovalent interaction has been put on the scene by highlighting its critical role in the mechanism of sulfide:quinone oxidoreductase. In the first step of the enzymatic mechanism, an anionic intermediate is formed and is stabilized by an anion–π interaction that involves a cysteine residue and a flavin adenine dinucleotide (FAD) molecule. In the Cover picture, a dragon spits fireballs that represent the sulfur atoms of the two cysteine residues of the active site (disulfide bridge), of which one interacts with the FAD molecule placed on a branch.

Copper-Catalyzed P-Arylation via Direct Coupling of Diaryliodonium Salts with Phosphorus Nucleophiles at Room Temperature

A new method for copper-catalyzed P-C bond formation through reaction of phosphorus nucleophiles with diaryliodonium salts at room temperature is described. Most target products are obtained with this method in high yields within a short reaction time of 10 min. It can be easily adapted to large-scale preparations. When unsymmetrical iodonium salts are employed, nucleophilic substitution occurs preferentially on the sterically hindered aromatic ring or the more electron-deficient ring.

Two Isostructural Explosive Cocrystals with Significantly Different Thermodynamic Stabilities

Irreconcilable differences: Electron-rich diacetone diperoxide is paired with the electron-deficient rings of trichloro- and tribromotrinitrobenzene to form energetic cocrystals by design. Though the two cocrystals are isostructural, the former is very stable while the later exhibits a rare metastability and favors separation.

Facile and Mild Displacement of Nitrite Ions in Electron-Deficient Nitroarenes by Alkyl or Aryl Thiols in the Presence of Magnesium Methoxide as a Solid Base Catalyst

The nucleophilic aromatic substitution reaction (S N Ar) between nitroarenes (having electron-withdrawing groups in the ­ortho or para position), and alkyl- or arylthiols using magnesium methoxide as a solid base catalyst is described. This method leads to the creation of a series of valuable compounds from arylsulfides via nucleophilic displacement of the nitro group with the sulfanyl moiety. This facile method is a synthetically useful process, and it is significant that the nucleophile is promoted effectively by magnesium methoxide as a base in N , N -dimethylformamide. The displacement of then nitrite ion occurred in the presence of a variety of functional groups that caused an electron-deficient ring such as aldehyde, ketone, ester, cyano, and nitro groups.

Photophysical and Electrochemical Properties of Donor–Acceptor Conjugated Oligomers Based on 3,4-Ethylenedioxythiophene and Deficient Rings

The photophysical and electrochemical properties of four novel donor-accepter (D-A) conjugated oligomers a-d based on 3,4-ethylenedioxythiophene (EDOT) and electrondeficient heterocycle rings were investigated. The UV-vis absorption spectroscopy, fluorescence emission spectroscopy and cyclic voltammertry studies suggest that the oligomers are expected to provide enhanced charge-transporting properties for the development of efficient electroluminescent materials. Furthermore, the third-order nonlinear optical (NLO) measurements made by Z-scan technique indicate that they have good third-order NLO response and are desired materias for fabricating nonlinear photonic devices. In the solid state of these oligomers, a strong tendency of self-assembled structure was also revealed by X-ray diffraction (XRD) patterns in powder.

A Divergent and Selective Synthesis of Isomeric Benzoxazoles from a Single N–Cl Imine

A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-hydroxyaryl N-H ketimines is described. The reaction proceeds in two distinct pathways through a common N-Cl imine intermediate: (a) N-O bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole, respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the rearrangement and the electron-deficient rings favoring the N-O bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl migration for the formation of 2-substituted benzoxazole is proposed.