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.

Effect of Bulky N-Dibenzofuranylmethyl Substitution on the 5-HT2 Receptor Affinity and Efficacy of a Psychedelic Phenethylamine.

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.

Structural modification of C2-substituents on 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives as potent inhibitors of the Keap1-Nrf2 protein-protein interaction.

The Keap1-Nrf2-ARE signaling pathway is an attractive therapeutic target for the prevention and treatment of oxidative stress-associated diseases by activating the cellular expression of cytoprotective enzymes and proteins. Small molecule inhibitors can directly disrupt the Keap1-Nrf2 protein-protein interaction (PPI), resulting in elevated levels of Nrf2 protein and subsequent stimulation of related antioxidant responses. Previously, we found that 1,4-bis(arylsulfonamido)benzene or naphthalene-N,N'-diacetic acid derivatives with an ether type C2-substituent on the benzene or naphthalene core exhibited potent inhibitory activities with IC50's in the submicromolar or nanomolar range. We here describe a more detailed structure-activity relationship study around the C2 substituents containing various polar linkers shedding new insight on their binding interactions with the Keap1 Kelch domain. The key observation from our findings is that the substituents at the C2-position of the benzene or naphthalene scaffold impact their inhibitory potencies in biochemical assays as well as activities in cell culture. The biochemical FP and TR-FRET assays revealed that the naphthalene derivatives 17b and 18 with an additional carboxylate at the C2 were the most active inhibitors against Keap1-Nrf2 PPI. In the cell-based assay, the two compounds were shown to be potent Nrf2 activators of the transcription of the Nrf2-dependent genes, such as HMOX2, GSTM3, and NQO1.

Effects of the aldehyde-derived ring substituent on the properties of two new bioinspired trimethoxybenzoylhydrazones: methyl vs nitro groups.

N-Acylhydrazones are a versatile class of organic compounds with a diversity of potential applications. In this study, two new structure-related 3,4,5-trimethoxybenzoyl-containing N-acylhydrazones were synthesized and fully characterized, both in solution and in the solid state. The compounds differ with respect to the carbonyl precursors, i.e., 3-substituted salicylaldehydes with either a methyl or a nitro group. Single crystals of both compounds were isolated from the respective mother liquors and, in both cases, XRD confirmed the obtention of the (E)-isomer, in an anti-conformation. Computational calculations (gas and water phases) were performed in order to confirm some of the structural and vibrational aspects of the compounds. An important intramolecular H bond involving the phenolic hydroxy group and the azomethine nitrogen was identified in the solid state and seems to be maintained in solution. Moreover, the presence of the electron-withdrawing nitro substituent makes this interaction stronger. However, the contact should probably not subsist for the nitro compound under physiological conditions since the presence of this substituent significantly affects the pKa of the phenol: an apparent value of 5.68 ± 0.02 was obtained. This also impacts the basicity of the azomethine nitrogen and, as a consequence, increases the hydrazone's susceptibility to hydrolysis. Nevertheless, both compounds are stable at physiological-like conditions, especially the methyl-derived one, which qualifies them for further toxicological and activity studies, such as those involving trivalent metal ions sequestering in the context of neurodegenerative diseases.

A comprehensive analysis of charge transfer effects on donor-pyrene (bridge)-acceptor systems using different substituents.

The alternant polycyclic aromatic hydrocarbon pyrene has photophysical properties that can be tuned with different donor and acceptor substituents. Recently, a D (donor)-Pyrene (bridge)-A (acceptor) system, DPA, with the electron donor N,N-dimethylaniline (DMA), and the electron acceptor trifluoromethylphenyl (TFM), was investigated by means of time-resolved spectroscopic measurements (J. Phys. Chem. Lett. 2021, 12, 2226-2231). DPA shows great promise for potential applications in organic electronic devices. In this work, we used the ab initio second-order algebraic diagrammatic construction method ADC(2) to investigate the excited-state properties of a series of analogous DPA systems, including the originally synthesized DPAs. The additionally investigated substituents were amino, fluorine, and methoxy as donors and nitrile and nitro groups as acceptors. The focus of this work was on characterizing the lowest excited singlet states regarding charge transfer (CT) and local excitation (LE) characters. For the DMA-pyrene-TFM system, the ADC(2) calculations show two initial electronic states relevant for interpreting the photodynamics. The bright S1 state is locally excited within the pyrene moiety, and an S2 state is localized ~0.5 eV above S1 and characterized as a donor to pyrene CT state. HOMO and LUMO energies were employed to assess the efficiency of the DPA compounds for organic photovoltaics (OPVs). HOMO-LUMO and optical gaps were used to estimate power conversion and light-harvesting efficiencies for practical applications in organic solar cells. Considering the systems using smaller D/A substituents, compounds with the strong acceptor NO2 substituent group show enhanced CT and promising properties for use in OPVs. Some of the other compounds with small substituents are also found to be competitive in this regard.

A Study of the Correlation between the Bulkiness of peri-Substituents and the Distortion of a Naphthalene Ring.

A systematic study on the distortion of a naphthalene ring was performed using steric repulsion between peri-substituents at the 1- and 8-positions. The introduction of bromo groups into the methyl groups of the 1,8-dimethylnaphthalene enhanced the steric repulsion to distort the naphthalene ring. X-ray crystallography revealed that 1,8-bis(bromomethyl)naphthalene had a vertical distortion with a 11.0° dihedral angle (α) between peri-substituents which disturbed the coplanarity of the naphthalene ring. On the other hand, the dihedral angle of 1,8-bis(dibromomethyl)naphthalene was smaller (α = 8.3°) despite the bulkier substituents. In this case, horizontal distortion of the naphthalene ring increased. These distortions should non-electronically activate the naphthalene framework. In order to evaluate their reactivity, nitration and hydrogenation were carried out; however, the 1,8-bis(dibromomethyl)naphthalene was intact under the employed conditions. A DFT calculation suggested that the inertness of the 1,8-bis(dibromomethyl)naphthalene is presumably due to the negative hyperconjugation of the (dibromo)methyl group.

Effect of Substituent Groups on the Strength of Intramolecular Hydrogen Bonds in 2,4-Dihydroxybenzophenone UV Absorbers.

2,4-Dihydroxybenzophenone is the most widely used molecule in the benzophenone group of UV absorbers. It is known that the UV absorption ability is dependent on the substituents. Numerous studies have shown that the strength of intramolecular hydrogen bonds is the main factor affecting this type of UV absorber. However, the effect of substituents on the formation and nature of the hydrogen bonds has not been well studied. In this work, the effect of the type of substituent and the substitution position on the absorption intensity of 2,4-dihydroxybenzophenone molecules is verified both experimentally and theoretically. The effect of substituents on the intramolecular hydrogen bonding of 2,4-dihydroxybenzophenone was investigated by DFT calculations. The results indicate that the addition of different substituents leads to various changes in the strength of the hydrogen bonding in 2,4-dihydroxybenzophenone. On the X-substitution site or the Y-substitution site, halogen groups and electron-absorbing groups such as -CN and -NO2 increase the strength of the hydrogen bond, while electron-giving groups such as -N(CH3)2 and -OCH3 decrease the strength of the bond. For the same substituent, the one at the Y site has a higher effect on hydrogen bonding than that at the X site. By NBO analysis, it was found that the substituents would cause charge redistribution of the individual atoms of 2,4-dihydroxybenzophenones, thus affecting the formation and strength of the hydrogen bonds. Moreover, when the substituent is at the Y substitution site, the oxygen atom of the carbonyl group is less able to absorb electrons and more charge is attracted to the oxygen atom of the hydroxyl group, resulting in a larger charge difference between the two oxygen atoms and an increase of bond energy. Finally, a multiple linear regression analysis of the NPA charge number of the atoms involved in the formation of the hydrogen-bonded chelated six-membered ring was performed with the energy of the hydrogen bond and the percentage of influencing factors estimated, which were found to jointly affect the strength of hydrogen bonding. The aim of this study is to provide theoretical guidance for the design of benzophenone-based UV absorbers that absorb UV light of specific wavelength bands.

Mechanofluorochromic behaviours of functionalized carbazole-based difluoroboron compounds with different aryl substituents moieties.

To better understand the relationship between molecular structure and mechanofluorochromic characteristics, three carbazole-based N^O-chelated difluoroboron compounds (Cz-S-BF2 , Cz-PhNp-S-BF2 , and Cz-BNp-S-BF2 ) with different aryl substituents moieties were designed and synthesized. The mechanofluorochromic behaviours of Cz-S-BF2 (luminescence from bluish-green to yellowish-green, emission from 504 to 535 nm) without aryl substitution and Cz-PhNp-S-BF2 (luminescence from green and yellow, emission from 521 to 557 nm) with a phenyl-naphthalene group underwent reversible conversion using the grinding-fuming process. For Cz-BNp-S-BF2 this was not apparent due to the well coplanarity of the binaphthalene moiety. Mechanofluorochromic properties were demonstrated through XRD patterns measurement. We envisage that this study will provide a practicable reference to acquire organic molecules with mechanofluorochromic characteristics.

Substituents Regulate the Cyclization of Conjugated Alkynes to Accurately Construct Cyclo-(E)-[3]dendralenes.

Substituent-regulated cyclization of conjugated alkynes with acid catalysis was developed in this paper, and it provides a straightforward synthesis of cyclic-(E)-[3]dendralenes. Depending on the electronic effect of the aromatic ring pairing, a variety of phosphinyl quintuplet/hexa cyclo-[3]dendralenes with diverse substitution patterns are accessible, with good efficiency and high stereoselectivity. This self-cyclization process achieves the first precise construction of a phosphinylcyclo-(E)-[3]dendralene from conjugated alkynes to aromatization.

Syntheses of Hindered-Polymethylacridinium Esters with Potential for Biological Probe Nanoarchitectonics.

Novel acridinium esters containing several methyl groups, at least one of which is in the 1 or 8-position, have been synthesized and their structures established. The influence of the methyl substituents on the chemiluminescent properties of the synthesized acridinium esters has been investigated.

Octafluoro-Substituted Phthalocyanines of Zinc, Cobalt, and Vanadyl: Single Crystal Structure, Spectral Study and Oriented Thin Films.

In this work, octafluoro-substituted phthalocyanines of zinc, vanadyl, and cobalt (MPcF8, M = Zn(II), Co(II), VO) were synthesized and studied. The structures of single crystals of the obtained phthalocyanines were determined. To visualize and compare intermolecular contacts in MPcF8, an analysis of Hirshfeld surfaces (HS) was performed. MPcF8 nanoscale thickness films were deposited by organic molecular beam deposition technique and their structure and orientation were studied using X-ray diffraction. Comparison of X-ray diffraction patterns of thin films with the calculated diffractograms showed that all three films consisted of a single crystal phase, which corresponded to a phase of single crystals. Only one strong diffraction peak corresponding to the plane (001) was observed on the diffraction pattern of each film, which indicated a strong preferred orientation with the vast majority of crystallites oriented with a (001) crystallographic plane parallel to the substrate surface. The effect of the central metals on the electronic absorption and vibrational spectra of the studied phthalocyanines as well as on the electrical conductivity of their films is also discussed.

Tuning the pH of Activation of Fluorinated Hydrazone-Based Switches─A Pathway to Versatile 19F Magnetic Resonance Imaging Contrast Agents.

Molecular switches have become an area of great interest in recent years. They are explored as high-density data storage and organic diodes in molecular electronics as well as chemosensors due to their ability to undergo a transition between well-defined structures under the action of external stimuli. One of the types of such switches is hydrazones. They work by changing the configuration from E to Z under the influence of pH or light. The change in configuration is accompanied by a change in the absorption band and changes in the nuclear magnetic resonance (NMR) spectrum. In this publication, the structure-property relationship of fluorinated hydrazone switches was established. A linear relationship between the Hammett substituent constants and the pH where the switching occurs was found. Introduction of strong electron-donating groups allowed obtaining a hydrazone switch of pKa = 6 suitable for application in 19F MRI as contrast agents.

Synthesis, Optical Properties, and Fluorescence Cell Imaging of Novel Mixed Fluorinated Subphthalocyanines.

Subphthalocyanines (SubPcs) are a kind of tripyrrolic macrocycle with a boron atom at their core. Incorporating different units onto the SubPc periphery can endow them with various unique properties. Herein, a series of novel fluorinated low-symmetry SubPc derivatives containing chlorine groups (F8-Cl4-SubPc, F4-Cl8-SubPc) and methoxy groups (F8-(OCH3)2-SubPc) were synthesized and characterized by spectral methods (MS, FT-IR, 1H, 13C, 11B, and 19F NMR spectroscopy), and the effect of the peripheral substituents on their electronic structure of low-symmetry macrocycle was investigated by cyclic voltammetry, theoretical calculation, electronic absorption, and emission spectroscopy. In contrast to perfluorinated SubPcs, these low-symmetry SubPcs revealed non-degenerate LUMO and LUMO + 1 orbitals, especially F8-(OCH3)2-SubPc, which was consistent with the split Q-band absorptions. The cyclic voltammetry revealed that these SubPcs exhibited two or three reduction waves and one oxidation wave, which is consistent with the reported SubPcs. Finally, an intracellular fluorescence imaging study of these compounds revealed that these compounds could enter cancer cells and be entrapped in the lysosomes, which provides a possibility of future applications in lysosome fluorescence imaging and targeting.

Novel amino analogs of the trimethoxyphenyl ring in potent colchicine site ligands improve solubility by the masked polar group incorporation (MPGI) strategy.

The low aqueous solubility of colchicine site antimitotic agents, of which the trimethoxyphenyl (A ring) is a heavy contributor, is a serious drawback in their clinical development. We have designed new A ring analogs with chameleonic masked polar amino groups able to increase aqueous solubility and also behave as non-polar through intramolecular hydrogen bonds when bound to tubulin. We have incorporated these new A rings in several scaffolds (sulfonamides, combretastatins, phenstatins, isocombretastatins), synthesized, and assayed 43 representatives. The amino analogs show improved aqueous solubility and some of them (8, 60Z, and 67) nanomolar anti-proliferative potencies against human cancer cell lines, with the most favorable substituent being a 3-methylamino group. The antiproliferative effect relates to tubulin inhibition as shown by in vitro tubulin polymerization inhibition, immunofluorescence microscopy, and cell cycle and apoptosis analysis by flow cytometry. The compounds arrest the cell cycle of treated cells in G2/M and later develop an apoptotic response. Docking studies suggested binding at the colchicine site of tubulin with good agreement with the DFT models of the new structural variations made. The 3-methylamino-4,5­dimethoxyphenyl moiety is an example of the masked polar group incorporation (MPGI) strategy for soluble ligands binding to hydrophobic sites and a good trimethoxyphenyl ring replacement for the development of new colchicine site ligands.

Triel Bonds with Au Atoms as Electron Donors.

The novel triel bonds of BX3 (X=H, F, Cl, Br, and I) and C5 H5 B as electron acceptors and AuR2 (R=Cl and CH3 ) as an electron donor were explored. The triel bond is a primary driving force for most complexes, while the contribution from a halogen-chlorine interaction in BX3 -AuCl2 (X=Cl, Br, and I) and an iodine-Au interaction in BI3 -Au(CH3 )3 is also very important. Interestingly, the positively charged Au atom of AuCl2 can attractively bind with the holes of BX3 and C5 H5 B. The interaction energy lies in the range of 1 and 80 kcal/mol, in the order X=F

Carbazole-based aggregation-induced phosphorescent emission-active gold(I) complexes with various phosphorescent mechanochromisms.

A series of carbazole-containing gold(I) complexes modified with different substituents were successfully designed and synthesized, and their molecular structures were characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. The aggregation-induced behaviors of these gold(I) complexes were studied by ultraviolet/visible and photoluminescence spectroscopy. Meanwhile, their mechanical force-responsive emissive properties were also investigated via solid-state photoluminescence spectroscopy. Interestingly, all these gold(I)-based luminogenic molecules were capable of exhibiting aggregation-induced phosphorescent emission phenomena. Furthermore, their solids of three gold(I) complexes displayed contrasting mechano-responsive phosphorescence features. More specifically, trifluoromethyl or methoxyl-substituted luminophores 1 and 3 demonstrated mechanochromic behaviors involving blue-shifted phosphorescence changes, and their mechanoluminochromic phenomena were reversible. However, the solid-state phosphorescence of phenyl-substituted luminophor 2 was not sensitive to external mechanical force.

The Steric Effect in Preparations of Vanadium(II)/(III) Dinitrogen Complexes of Triamidoamine Ligands Bearing Bulky Substituents.

The reactions of newly designed lithiated triamidoamines Li3LR (R = iPr, Pen, and Cy2) with VCl3(THF)3 under N2 yielded dinitrogen-divanadium complexes with a µ-N2 between vanadium atoms [{V(LR)}2(µ-N2)] (R = iPr (1) and Pen (2)) for the former two, while not dinitrogen-divanadium complexes but a mononuclear vanadium complex with a vacant site, [V(LCy2)] (R = Cy2 (3)), were obtained for the third ligand. The V-NN2 and N-N distances were 1.7655(18) and 1.219(4) Å for 1 and 1.7935(14) and 1.226(3) Å for 2, respectively. The ν(14N-14N) stretching vibrations of 1 and 2, as measured using resonance Raman spectroscopy, were detected at 1436 and 1412 cm-1, respectively. Complex 3 reacted with potassium metal in the presence of 18-crown-6-ether under N2 to give a hetero-dinuclear vanadium complex with µ-N2 between vanadium and potassium, [VK(LCy2)(µ-N2)(18-crown-6)] (4). The N-N distance and ν(14N-14N) stretching for 4 were 1.152(3) Å and 1818 cm-1, respectively, suggesting that 4 is more activated than complexes 1 and 2. The complexes 1, 2, 3, and 4 reacted with HOTf and K[C10H8] to give NH3 and N2H4. The yields of NH3 and N2H4 (per V atom) were 47 and 11% for 1, 38 and 16% for 2, 77 and 7% for 3, and 80 and 5% for 4, respectively, and 3 and 4, which have a ligand LCy2, showed higher reactivity than 1 and 2.

Highly Efficient Deep-Blue Phosphorescent OLEDs Based on a Trimethylsilyl-Substituted Tetradentate Pt(II) Complex.

Compared to Ir(III) complexes with octahedral geometries, Pt(II) complexes with square planar geometries show superior optical properties because their flat shapes lead to an orientation that enhances the outcoupling of organic light-emitting diodes (OLEDs). However, the flat shapes of Pt(II) complexes typically induce a bathochromic shift, limiting their application in high-performance deep-blue phosphorescent OLEDs with high color purity. In this study, bulky trimethylsilyl (TMS)-substituted blue phosphorescent Pt(II) complex (PtON7-TMS) is successfully synthesized to improve color purity. The TMS substituent containing Si atom effectively suppresses intermolecular interaction and aggregation even when the complex concentration in the film state is higher than 30 wt %. As a result, the PtON7-TMS-based OLEDs exhibit a maximum external quantum efficiency of 21.4%, along with a pure-blue color of CIE (0.14, 0.09) at 20 wt % doping concentration and a full-width at half maximum of 30 nm. The pure blue color is maintained at a higher doping concentration (>30 wt %).

Ring replacement recommender: Ring modifications for improving biological activity.

Analysis of structure-activity data from a large corpus of medicinal chemistry literature identified a set of ring replacements that have a significant chance of improved biological activity. A database of these replacements for 245 common heterocyclic rings is provided. Based on the analysis of the whole data set, 80 diverse substituted rings are suggested for use in an early stage of hit optimization and in the design of focused libraries with the goal to explore structure-activity relationships and quickly improve the biological activity of the explored series. An easy to use Ring Replacement Recommender web tool, allowing medicinal chemists to interactively explore the recommended ring substitutions, is available at https://bit.ly/ringreplacement.

Free Metallophosphines: Extremely Electron-Rich Phosphorus Superbases That Are Electronically and Sterically Tunable.

We report herein a facile and highly modular access to an intriguing class of free Au-substituted phosphines (AuPhos), namely (LAu)n PR3-n (L=singlet carbene ligand; R=H, aryl, alkyl, silyl) (n=1-3). The Tolman electronic parameter (TEP) values coupled with theoretical investigations showcase that Au-substitution can boost the electron-releasing ability of AuPhos, thus leading to an electronically and sterically tunable, extremely electron-rich phosphorus center. The high basicity of AuPhos is attributed to the d-p lone pair π-repulsion arising from interaction between Au substituents and the lone pair at P. A series of multi-nuclear transition metal complexes (i.e. Rh, Ir, Pd, Au, W, Mn) ligated by AuPhos are readily prepared via a straightforward process. Preliminary catalytic results reveal the facilitation of Pd-catalyzed C-N coupling reactions and Ir-catalyzed decarbonylation reactions via AuPhos. This work provides insights for future development of electron-rich ligands.