Regular Arrays of Rod-Shaped Molecular Photoswitches: Synthesis, Preparation, Characterization, and Selective Photoswitching within Mono- and Bilayer Systems.

We assembled photoresponsive mono- and bilayer systems with well-defined properties from rod-shaped molecules equipped with different photoswitches. Using properly chosen chromophores (diarylethene-based switch and unidirectional light-driven molecular motor), we then selectively targeted layers made of the same types of photoswitches using appropriate monochromatic light. UV-vis analysis confirmed smooth and unrestricted photoisomerization. To achieve this, we synthesized a new class of triptycene-based molecular pedestals adept at forming sturdy Langmuir-Blodgett films on a water-air interface. The films were smoothly transferred to gold and quartz surfaces. Repeated deposition afforded bilayer systems: one layer containing diarylethene-based photoswitches and the other a unidirectional light-driven molecular motor. Structural analysis of both mono- and bilayer systems revealed the molecules to be tilted with carboxylic functions pointing to the surface. At least two different polymorphs differing in monolayer thickness and tilt angle (~40° and ~60°) were identified on the gold surface.

Resolution of 9,10-Diketo[7]helicene and Its Use in One-Step Preparation of Helicene-Based D-A-D Push-Pull Systems.

Racemic 9,10-diketo[7]helicene was successfully separated into enantiomers using a reversible and stereoselective reaction with 2,2'-diamino-1,1'-binaphthalene with moderate yields but with remarkable purity (>99% de). The enantiomerically pure diketone was used as a convenient starting material for the preparation of helicene-based push-pull molecules, which incorporated aza-aryl acceptors and diarylaminophenylene donor groups in a single step. A series of six push-pull systems, along with three reference molecules without donors, were prepared and studied using UV/vis and fluorescence measurements, circular dichroism, and DFT calculations.

Spatial arrangements of cyclodextrin host-guest complexes in solution studied by 13C NMR and molecular modelling.

13C NMR spectroscopic analyses of Cs symmetric guest molecules in the cyclodextrin host cavity, combined with molecular modelling and solid-state X-ray analysis, provides a detailed description of the spatial arrangement of cyclodextrin host-guest complexes in solution. The chiral cavity of the cyclodextrin molecule creates an anisotropic environment for the guest molecule resulting in a splitting of its prochiral carbon signals in 13C NMR spectra. This signal split can be correlated to the distance of the guest atoms from the wall of the host cavity and to the spatial separation of binding sites preferred by pairs of prochiral carbon atoms. These measurements complement traditional solid-state analyses, which rely on the crystallization of host-guest complexes and their crystallographic analysis.

Cyclotrimerization Approach to Symmetric [9]Helical Indenofluorenes: Diverting Cyclization Pathways.

Catalytic cyclotrimerization routes to symmetrical [9]helical indenofluorene were explored by using different transition-metal complexes and thermal conditions. Depending on the reaction conditions, the cyclotrimerizations were accompanied by dehydro-Diels-Alder reaction giving rise to another type of aromatic compounds. Structures of both symmetrical [9]helical cyclotrimerization product as well as the dehydro-Diels-Alder product were confirmed by single-crystal X-ray diffraction analyses. Limits of enantioselective cyclotrimerization were assessed as well. DFT calculations shed light on the reaction course and the origin of diminished enantioselectivity.

Access to Spirooxindole-Fused Cyclopentanes via a Stereoselective Organocascade Reaction Using Bifunctional Catalysis.

The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1-nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-to-good isolated yields (15-69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxindole compounds.

Enantioenriched 1,4-Benzoxazepines via Chiral Brønsted Acid-Catalyzed Enantioselective Desymmetrization of 3-Substituted Oxetanes.

Herein, we present a highly enantioselective desymmetrization of 3-substituted oxetanes enabled by a confined chiral phosphoric acid. This metal-free process allows effective access to chiral seven-membered 1,4-benzoxazepines with a high degree of enantiocontrol, under mild reaction conditions. The developed synthetic strategy tolerates a broad substrate scope and demonstrates its synthetic utility in various enantioselective product transformations, thus proving its effectiveness in diverse scenarios.

Chlorinated Cubane-1,4-dicarboxylic Acids.

Herein, we report radical chlorination of cubane-1,4-dicarboxylic acid leading preferentially to one monochlorinated cubane dicarboxylate (ca. 70%) that is accompanied by four dichlorinated derivatives (ca. 20% in total). The exact positions of the chlorine atoms have been confirmed by X-ray diffraction of the corresponding single crystals. The acidity constants of all dicarboxylic acids in water were determined by capillary electrophoresis (3.17 ± 0.04 and 4.09 ± 0.05 for monochlorinated and ca. 2.71 ± 0.05 and 3.75 ± 0.05 for dichlorinated cubanes). All chlorinated derivatives as well as the parent diacid showed high thermal stability (decomposition above 250 °C) as documented by differential scanning calorimetry. The probable reaction pathways leading to individual isomers were proposed, and the energies of individual transition states and intermediates were obtained using density functional theory calculations (B3LYP-D3BJ/6-311+G(d,p)). The relative strain energies for all newly prepared derivatives as well as for hypothetical hexahalogenated (fluorinated, chlorinated, brominated, and iodinated) derivatives of cubane-1,4-dicarboxylic acids were predicted using wavefunction theory methods. The hexafluorinated derivative was identified as the most strained compound (57.5 kcal/mol), and the relative strain decreased as the size of halogen atoms increased (23.7 for hexachloro, 16.7 for hexabromo, and 4.0 kcal/mol for the hexaiodo derivative).

Synthesis, Structure, Reactivity, and Intramolecular Donor-Acceptor Interactions in a Phosphinoferrocene Stibine and Its Corresponding Phosphine Chalcogenides and Stiboranes.

Ferrocene-based phosphines equipped with additional functional groups are versatile ligands for coordination chemistry and catalysis. This contribution describes a new compound of this type, combining phosphine and stibine groups at the ferrocene backbone, viz. 1-(diphenylphosphino)-1'-(diphenylstibino)ferrocene (1). Phosphinostibine 1 and the corresponding P-chalcogenide derivatives Ph2P(E)fcSbPh2 (1E, fc = ferrocene-1,1'-diyl, E = O, S, Se) were synthesized and further converted to the corresponding stiboranes Ph2P(E)fcSb(O2C6Cl4)Ph2 (6 and 6E) by oxidation with o-chloranil. All compounds were characterized by spectroscopic methods, X-ray diffraction analysis, cyclic voltammetry, and theoretical methods. Both NMR spectroscopy and DFT calculations confirmed the presence of P → Sb and P═O → Sb donor-acceptor interactions in 6 and 6O, triggered by the oxidation of the stibine moiety into Lewis acidic stiborane. The corresponding interactions in 6S and 6Se were of the same type but significantly weaker. A coordination study with AuCl as the model metal fragment revealed that the phosphine group acts as the "primary" coordination site, in line with its higher basicity. The obtained Au(I) complexes were applied as catalysts in the Au-catalyzed cyclization of N-propargylbenzamide and in the oxidative [2 + 2 + 1] cyclization of ethynylbenzene with acetonitrile and pyridine N-oxides. The catalytic results showed that the stibine complexes had worse catalytic performance than their phosphine counterparts, most likely due to the formation of weaker coordination bonds and hence poorer stabilization of the active metal species. Nevertheless, the stibine moiety could be used to fine-tune the properties of the ligated metal center by changing the oxidation state or substituents at the "remote" Sb atom.

Resolution by diastereomeric salts: Access to both enantiomers of racemic acid using the same enantiomer of resolving base.

Racemic carboxylic acid, a Diels-Alder cycloadduct derived from 5-bromo-3-phenyl-α-pyrone and acrylate dienophile, was resolved into enantiomers by diastereomeric salt crystallization. Quinidine was used as a sole resolving base. The salt of (+)-acid crystallized from aqueous acetonitrile solution. Once this salt was separated by filtration, quinidine salt with (-)-acid crystallized from mother liquor. As a result, both enantiomers of Diels-Alder cycloadduct were isolated in high enantiomeric purity.

Importance of Nuclear Quantum Effects for Molecular Cocrystals with Short Hydrogen Bonds.

Many efforts have been recently devoted to the design and investigation of multicomponent pharmaceutical solids, such as salts and cocrystals. The experimental distinction between these solid forms is often challenging. Here, we show that the transformation of a salt into a cocrystal with a short hydrogen bond does not occur as a sharp phase transition but rather a smooth shift of the positional probability of the hydrogen atoms. A combination of solid-state NMR spectroscopy, X-ray diffraction, and diffuse reflectance measurements with density functional theory calculations that include nuclear quantum effects (NQEs) provides evidence of temperature-induced hydrogen atom shift in cocrystals with short hydrogen bonds. We demonstrate that for the predictions of the salt/cocrystal solid forms with short H-bonds, the computations have to include NQEs (particularly hydrogen nuclei delocalization) and temperature effects.

Diketo-Ketoenol Tautomers in Curcuminoids: Synthesis, Separation of Tautomers, and Kinetic and Structural Studies.

Curcumin and its congeners exist in an equilibrium between diketo and ketoenol tautomers, which have different potencies to bind biomolecules. This work describes procedures for the preparation of 4-alkylated curcumin derivatives and the separation of their two tautomeric forms. Comprehensive NMR studies of the tautomer equilibria in various solvents have been accomplished. Additionally, a pure ketoenol tautomeric form of the active pharmaceutical ingredient (API) ASC-JM17 has been unequivocally determined by X-ray crystallography. Two different polymorphs of this API have been microscopically identified in the X-ray sample and manually separated, and a solid-state NMR study of the two polymorphs has also been performed. This work reports on the slow kinetics of diketo-ketoenol tautomerization in particular solvents that allow the separation and full characterization of both curcuminoids' tautomers.

Ir-Catalyzed Cycloaddition of Tribenzocyclyne with Biphenylenes.

We demonstrate that Ir-catalyzed C-C bond activation in biphenylenes followed by a reaction with tribenzocyclyne is a suitable method for synthesizing strained and unknown monoadducts with the tetradehydrotetrabenzo[a,c,e,i]cyclododecene scaffold ([12]annulenes). Modification of reaction conditions also furnished [12]annulene products with cis and/or trans double bonds formed by hydrogen transfer. The [9]annulene side product was formed upon the reaction of the benzyl radical with tribenzocyclyne during the Bergman cyclization. All isolated compounds were fully characterized by HRMS, NMR, and X-ray diffraction analysis.

Synthesis of Aza[n]helicenes (n = 4-7) via Photocyclodehydrochlorination of 1-Chloro-N-aryl-2-naphthamides.

A series of aza[n]helicenes (n = 4-7) was synthesized using a photocyclodehydrochlorination of 1-chloro-N-aryl-2-naphthamides as a general synthetic procedure introducing the nitrogen atom to the third ring of the helicene framework. The effect of the nitrogen presence in the helicene skeleton on the physicochemical properties of the prepared aza[n]helicenes was studied and compared to those of the parent carbo-analogues. The insertion of a nitrogen atom into the outer edge of the helicene molecule has a severe impact on certain physicochemical properties such as optical rotation, electrostatic potentials, and intermolecular interactions. On the other hand, some other properties such as UV/vis, fluorescence, and phosphorescence spectra remained almost unaffected when compared to the parent carbohelicenes. A nitrogen atom can be also used for further derivatization, which can lead to further modification of helicene properties, as manifested here in the fluorescence changes induced by protonation.

Silicon-bridged (1→1)-disaccharides: an umpoled glycomimetic scaffold.

Modification of the carbohydrate scaffold is an important theme in drug and vaccine discovery. Therefore, the preparation of novel types of glycomimetics is of interest in synthetic carbohydrate chemistry. In this manuscript, we present an early investigation of the synthesis, structure, and conformational behaviour of (1→1)-Si-disaccharides as a novel type of glycomimetics arising from the replacement of interglycosidic oxygen with a dimethyl-, methylpropyl-, or diisopropylsilyl linkage. We accomplished the preparation of this unusual group of umpoled compounds by the reaction of lithiated glycal or 2-oxyglycal units with dialkyldichlorosilanes. We demonstrated the good stability of the "Si-glycosidic" linkage under acidic conditions even at elevated temperatures. Next, we described the conformational landscape of these compounds by the combination of in silico modelling with spectroscopic and crystallographic methods. Finally, we explained the observed conformational flexibility of these compounds by the absence of gauche stabilizing effects that are typically at play in natural carbohydrates.

The Effect of Deoxyfluorination on Intermolecular Interactions in the Crystal Structures of 1,6-Anhydro-2,3-epimino-hexopyranoses.

The effect of substitution on intermolecular interactions was investigated in a series of 1,6-anhydro-2,3-epimino-hexopyranoses. The study focused on the qualitative evaluation of intermolecular interactions using DFT calculations and the comparison of molecular arrangements in the crystal lattice. Altogether, ten crystal structures were compared, including two structures of C4-deoxygenated, four C4-deoxyfluorinated and four parent epimino pyranoses. It was found that the substitution of the original hydroxy group by hydrogen or fluorine leads to a weakening of the intermolecular interaction by approximately 4 kcal/mol. The strength of the intermolecular interactions was found to be in the following descending order: hydrogen bonding of hydroxy groups, hydrogen bonding of the amino group, interactions with fluorine and weak electrostatic interactions. The intermolecular interactions that involved fluorine atom were rather weak; however, they were often supported by other weak interactions. The fluorine atom was not able to substitute the role of the hydroxy group in molecular packing and the fluorine atoms interacted only weakly with the hydrogen atoms located at electropositive regions of the carbohydrate molecules. However, the fluorine interaction was not restricted to a single molecule but was spread over at least three other molecules. This feature is a base for similar molecule arrangements in the structures of related compounds, as we found for the C4-Fax and C4-Feq epimines presented here.

A Stable Primary Phosphane Oxide and Its Heavier Congeners.

(Ferrocenylmethyl)phosphane (1) oxidation with hydrogen peroxide, elemental sulfur and grey selenium produced (ferrocenylmethyl)phosphane oxide 1O, sulfide 1S and selenide 1Se, respectively, as the first isolable primary phosphane chalcogenides lacking steric protection. At elevated temperatures, compound 1O disproportionated into 1 and (ferrocenylmethyl)phosphinic acid. In reactions with [(η6 -mes)RuCl2 ]2 , 1O underwent tautomerization into a phosphane complex [(η6 -mes)RuCl2 {FcCH2 PH(OH)-κP}], whereas 1S and 1Se lost their P-bound chalcogen atoms, giving rise to the phosphane complex [(η6 -mes)RuCl2 (FcCH2 PH2 -κP)] (Fc=ferrocenyl, mes=mesitylene). No tautomerization was observed in the reaction of 1O with B(C6 F5 )3 , which instead produced a Lewis pair FcCH2 P(O)H2 -B(C6 F5 )3 . Phosphane oxide 1O added to C=O bonds of aldehydes and ketones and even to cumulenes PhNCE (E=O and S). However, both PH hydrogens were only employed in the reactions with aldehydes and cyanates.

Rhodium-Catalyzed Enantioselective Synthesis of Highly Fluorescent and CPL-Active Dispiroindeno[2,1-c]fluorenes.

The enantioselective synthesis of chiral [7]-helical dispirodihydro[2,1-c]indenofluorenes (DSF-IFs) was achieved for the first time in good yields with high er values (er up to 99 : 1). The crucial step of the whole reaction sequence was the enantioselective intramolecular [2+2+2] cycloaddition of tethered triynediols to indenofluorenediols, which was catalyzed by a Rh/SEGPHOS® complex. Further transformations led to the corresponding DSF-IFs. The prepared helically chiral DSF-IFs combine circularly polarized luminescence (CPL) activity (glum =∼10-3 ) with exceptionally high fluorescence quantum yields (up to Φlum =0.97).

Enantioselective Construction of Chiral Bispiro[Oxindole-Pyrrolidine-Pyrazolone] Derivatives via Sequential and One-Pot Mannich/Hydroamination Reaction.

The atom-economic method for the preparation of novel bispirocyclic compounds containing three fused heterocyclic scaffolds privileged in drug discovery was developed by using a chiral amine-squaramide Mannich reaction and Au(I)-catalyzed hydroamination. The developed synthetic strategy performed either stepwise or as a one-pot process allows the formation of chiral bispirocyclic [oxindole-pyrrolidine-pyrazolones] in high yields (up to 75%) with excellent enantioselectivities (up to 99%).

Synthesis of Aza[n]phenacenes (n = 4-6) via Photocyclodehydrochlorination of 2-Chloro-N-aryl-1-naphthamides.

A novel methodology for the synthesis of aza[n]phenacenes was successfully developed utilizing photocyclodehydrochlorination reaction of 2-chloro-N-aryl-1-naphthamides. In these key intermediates, the factors influencing the photoreaction were studied. The target aza[n]phenacenes were obtained by triflation or chlorination from prepared phenanthridinones, followed by hydrogenation. The introduction of a nitrogen atom into a phenacene skeleton induced changes in the physicochemical properties. The important properties of prepared aza[n]phenacenes (n = 4-6) were studied experimentally and by density functional theory calculations and were compared to those of their carbo analogues. Furthermore, some important features of the crystalline aza[n]phenacenes were investigated, including intermolecular interaction in the crystal lattice and the increased solubility or decreased melting points.

Synthesis of cis-Oriented Vicinal Diphenylethylenes through a Lewis Acid-Promoted Annulation of Oxotriphenylhexanoates.

This study explores the synthesis of cyclic cis-vicinal phenyl ethylenes from oxotriphenylhexanoates. The reaction is a BBr3-promoted cyclization of 1,6-ketoesters (1) to five-membered diketo compounds (2). The synthesis is interesting as it constitutes one of the few examples of modular stereoselective synthesis of structures with a cis-oriented vicinal diphenylethylene. The core structure of 2 can be smoothly derivatized, which makes it a promising synthetic building block for further stereoselective synthetic applications.