Mono-N-8-alkyl and mono-N-8-aryl amide derivatives of the cobalt bis-dicarbollide complex anion [1-] were synthesized efficiently under mild conditions in acetonitrile using the B(8)ammonium cobalt bis-dicarbollide [3], N,N'-dicyclohexylcarbodiimide, triethylamine, and the corresponding organic acids. The resulting amide intermediates were subsequently converted into monoalkylated and monoarylated ammonium derivatives by reduction with a borane-tetrahydrofuran complex. In contrast, aluminum-based hydride reagents, including lithium aluminum hydride and diisobutylaluminum hydride, were found to be incompatible with this system. In parallel, selective synthetic procedures for the preparation of di- and trimethylated ammonium derivatives of [1-] were optimized using dimethyl sulfate, a suitable solvent, and a base. All compounds were characterized by nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, mass spectrometry, ultraviolet-visible spectroscopy, thin-layer chromatography, melting point, and elemental analysis, and the structure of the trimethylated derivative was confirmed by single-crystal X-ray diffraction.

The molecular structure and binding mechanisms of three isomeric molecular receptors (molecular tweezers of the bis-Troger's base type) were investigated using single-crystal X-ray diffraction of both the free receptors and their complexes with 1,2,4,5-tetracyanobenzene, molecular modeling, and binding isotherms obtained from 1H NMR titrations. The crystal structures reveal distinct conformations of the receptors and demonstrate that the guest can be bound either inside the tweezer's cavity or at external sites. The binding isotherms were evaluated using a custom open-source Python-based software tool, Binding Evaluation and Analysis Software Tool (BEAST), which considers binding stoichiometries HG, HAG, HGA, and HA. The reliability of the binding models is assessed using selected fitting criteria and statistical tests on residuals. The study reveals that each receptor behaves differently, allowing binding both inside and outside the tweezer's cavity. Moreover, the expected 1:1 stoichiometry (association constants 25 to 2600 M-1) is often followed by 2:1 stoichiometry (association constants 79 to 3180 M-2) and possibly also dimerization of the tweezers. This work demonstrates that reliable conclusions about the binding mechanisms of molecular receptors can only be derived through a combination of multiple analytical methods.

Abstract Trospium (TR) and exotrospium (ETR) form a closely related epimeric pair of quaternary ammonium compounds, differing only in the stereochemistry of the tropane ring system. While the solid-state chemistry of trospium has been studied mainly for its chloride salt, no crystal structures of exotrospium salts have previously been reported. Here, we investigate the epimer-dependent solid-state landscapes of TR and ETR across the halide series, using matched salt forms to distinguish the effects of counterion selection from those of stereochemical inversion. Two new TR salts and three new ETR salts were prepared and structurally characterized by single-crystal X-ray diffraction, supported by crystal-packing comparison, hydrogen-bond propensity analysis, lattice-energy calculations, morphology prediction, and CSD-Particle surface analysis. Despite their close molecular similarity, TR and ETR display markedly different solid-state behavior. TR forms anhydrous chloride, bromide, and iodide salts stabilized by direct charge-assisted O–H···halide interactions, whereas ETR forms isostructural chloride and bromide dihydrates, with only the iodide obtained as an anhydrate. These differences are reflected in molecular conformation, crystal packing, hydration behavior, predicted crystal habit, and surface descriptors. The results show that epimerization can substantially alter both bulk and surface features of pharmaceutical molecular salts and demonstrate the value of combining structural comparison with particle-level descriptors when evaluating related solid forms.

Accurate localization of hydrogen atoms in short intermolecular hydrogen bonds remains challenging in X-ray crystal structure analysis, particularly for systems near the salt-cocrystal boundary. Many such structures have been reported to exhibit hydrogen-atom disorder, raising questions about the underlying proton potential-energy landscape. Here, we combine Hirshfeld atom refinement (HAR) of X-ray diffraction data, solid-state NMR spectroscopy, and periodic density functional theory (DFT) calculations to re-examine hydrogen bonding in molecular crystals featuring short O-H & centerdot;& centerdot;& centerdot;N/N-H & centerdot;& centerdot;& centerdot;O contacts. We selected 29 candidate structures with reported hydrogen disorder; original diffraction data for 14 systems were rerefined using HAR, and several additional systems were newly crystallized and structurally redetermined. In all experimentally accessible cases, HAR refinements converged without disorder and yielded proton positions consistent with independent ssNMR measurements. Periodic DFT calculations revealed shallow and method-sensitive potential-energy surfaces for short hydrogen bonds, rationalizing the frequent misassignment of proton positions in conventional refinements. These results demonstrate that apparent hydrogen-atom disorder in short hydrogen bonds is predominantly an artifact of spherical-atom refinement models rather than evidence for genuine proton positional disorder. The results establish a robust experimental-theoretical framework for distinguishing between salt, cocrystal, and continuum structures.

With the aim to understand the role of the 2‐isopropoxybenzylidene ligand, we synthesized Hoveyda‐Grubbs 1st and 2nd generation precatalysts (HG‐I and HG‐II) analogs modified in the phenyl ring with 5‐octyloxy, 5‐(3,3,4,4,5,5,6,6,7,7,8,8,8‐tridecafluorooctyloxy), 5‐(2,2,3,3,4,4,5,5,6,6,7,7,7‐tridecafluoroheptyloxy) or 5‐(2,2,4,4,5,5,7,7,7‐nonafluoro‐3,6‐dioxaheptyloxy) ponytails and/or instead of isopropoxy group with longer decan‐2‐yloxy or 5,5,6,6,7,7,8,8,9,9,10,10,10‐tridecafluorodecan‐2‐yloxy groups. To improve the fluorophilicity of the precatalysts, we further modified selected precatalysts by two or four 3,3,4,4,5,5,6,6,7,7,8,8,8‐tridecafluorooctyl ponytails in the NHC ligand. All modified HG‐I analogs were more active than precatalyst HG‐I in the ring‐closing metathesis (RCM) of diethyl allyl(methallyl)malonate (DEAMM, RCM3). On the other hand, only HG‐II complexes modified with fluorinated chain in the isopropoxy group surpassed commercial HG‐II precatalyst in the RCM3. In the most demanding RCM reaction of diethyl dimethallylmalonate (DEDMM, RCM4), both precatalysts modified with sec‐decyloxy group initiated more quickly than HG‐II, but seem to be less stable over long reaction times. Medium fluorous HG‐II analogs bearing two or three polyfluorinated chains in the alkoxybenzylidene ligand were successfully tested in repeated RCM3 using medium fluorous recycle. Release‐return mechanism, essential for medium fluorous recycle, was confirmed by partial exchange of the alkoxybenzylidene moieties in the recycled precatalysts using combinations of precatalysts and styrenes bearing different alkoxy groups.

Head and neck cancers remain among the most challenging malignancies to treat and are often linked to lifestyle-related risk factors such as smoking and alcohol consumption. These factors not only initiate tumor development but also promote chronic inflammation and activate key oncogenic pathways, including NF-κB signaling and pro-angiogenic cytokines IL-6 and IL-8. Research into emerging therapeutic approaches has identified metal-based compounds-especially ruthenium(II) complexes-as promising alternatives to traditional platinum-based drugs. In this study, we report the design, synthesis and X-RAY characterization of a ruthenium(II) complex incorporating a quinoline-chalcone hybrid ligand, designed for enhanced anticancer and anti-inflammatory potential. The resulting compound, referred to as complex 2, demonstrated significant activity against HPV-negative head and neck cancer cell lines. It exhibited strong cytostatic, antiproliferative, and migrastatic effects, along marked suppression of NF-κB activation and a notable decrease in IL-6 and IL-8 levels due to direct interactions. These findings highlight complex 2 as a promising multitarget agent capable of targeting both tumor progression and the inflammatory microenvironment. Overall, complex 2 is a potential candidate for combination therapies targeting head and neck cancer.

Apremilast is a poorly soluble active pharmaceutical ingredient. It is prone to form multicomponent crystals and crystallizes in very similar molecular arrangements. We have crystallized apremilast with derivatives of halogen benzoic acid. Such compounds are known to moderate crystallization processes to different polymorphs of paracetamol. Surprisingly, apremilast structure packing was able to accommodate the o- and m-halogen benzoic acid derivatives in the same structure type as for known structures. On the other hand, crystallization with p-halogen benzoic acid derivatives leads to a cocrystal form with a rare molecular arrangement, which is likely less stable, and hence not preferred in the structures with smaller co-formers. The new forms were characterized by Single Crystal and Powder X-Ray Diffraction, and their stability was studied and compared by Differential Scanning Calorimetry and Thermogravimetric Analysis.

Macrocyclic systems having a thiacalix[4]arene-like structure with four bridging sulfur atoms can be easily constructed using benzoquinone and dithiol-based building blocks. The conjugate addition of benzene-1,3-dithiol with two equivalents of 2,6-dimethylbenzoquinone afforded the corresponding hydroquinone trimer, which, after oxidation to benzoquinone, undergoes a final macrocyclization with another benzene-1,3-dithiol molecule. The whole sequence represents a new strategy for the synthesis of macrocycles based on thiacalix[4]arenes. The conformational behavior of these macrocycles was studied using nuclear magnetic resonance and X-ray analyses, and their basic redox properties were investigated with electrochemical methods.

Tröger's base analogs (TBAs) are tertiary diamines with twisted structures and asymmetric nitrogen atoms that can be isolated as enantiopure species. Coumarins are natural occurring oxygen carrying fluorophores with distinct biological and photophysical properties. The present research demonstrates how the combination of the chirality of TBAs and the fluorescence properties of coumarins can generate circularly polarized luminescence (CPL). We report here the preparation, enantiomeric separation, and chiroptical properties of Tröger's base analogs (TBAs) derived from aminocoumarins with methyl or trifluoromethyl group. All three possible TBAs are prepared, identified by nuclear magnetic resonance (NMR) and single crystal X-ray diffraction (SC-XRD), and resolved via chromatography on Whelk-O1 type phase. Absolute configurations of pure enantiomers are determined via SC-XRD and similarity of optical rotation, circular dichroism and CPL spectra. Modest CPL properties with dissymmetry factor ~ 10-3 were obtained. Additionally, we examined the effect of symmetry in the chiroptical properties of those coumarin-TBAs, and our results suggest that the TBAs subunits should be significantly more differentiated to improve their CPL properties.

Pharmaceutical solid forms, like salts and cocrystals, play a crucial role in drug formulation. Despite differing mainly by a single hydrogen atom, the regulatory requirements set by the US Food and Drug Administration for these forms vary significantly. We previously developed a DFT-based computational method to distinguish salts from cocrystals. This method, validated on 95 structures, performed well for systems where hydrogen bonds were longer than 2.613 (16) Å. Here, benefits of the rSCAN functional over the PBE functional are discussed. We expand the dataset to 404 cocrystal models. Analysis confirms that 301 of these forms are indeed cocrystals. Additionally, 87 salt–cocrystal continuum forms are identified and 16 cocrystals are classified as possible salts. These 16 problematic structures are further investigated and for seven of them, single crystals were grown and their structure determined using single-crystal X-ray diffraction. Among the phases exhibiting salt-like behaviour, five of them are identified as salts. In some cases, rSCAN alone gives unreliable results for strong hydrogen bonds, but these discrepancies are often corrected using better-renormalized or hybrid functionals ( i.e. r2SCAN, PBE0 and PBE50). For future calculations, we recommend using the r2SCAN functional for salt–cocrystal differentiation, as it provides reliable results for O—H...N bonds longer than 2.554 (5) Å. The r2SCAN functional offers a good balance between accuracy and computational efficiency for systems with longer O—H...N bonds.

The article describes a simple and scalable preparation of 2-monothiacalix[4]arene 7, the simplest representative of the mixed-bridged (CH2 and S) calix[4]arenes. The synthesis is based on the condensation of linear building blocks (bisphenols), which are relatively readily available, and allows, depending on the conditions, the use of two alternative reaction routes that provide macrocycle 7 in high yield. The dynamic behavior of the basic macrocyclic skeleton was investigated using NMR spectroscopy at variable temperatures. High-temperature measurements showed that compound 7 undergoes a cone–cone equilibrium with activation free energy ΔG# of the inversion process of 63 kJ·mol−1. Interestingly, the same barrier for the oxidized sulfone derivative 14 shows a value of 60 kJ·mol−1, indicating weakened hydrogen bonds at the lower rim of the calixarene. The same was also confirmed at low temperatures, when barriers to changing the direction of the cyclic hydrogen bond arrays (flip-flop mechanism) were determined (compare ΔG# = 44 kJ·mol−1 for 7 vs. ΔG# = 40 kJ·mol−1 for 14).

The most commonly used homogeneous catalyst for fatty acid esterification is a corrosive sulphuric acid. However, this requires costly investment in non-corrosive equipment, presents a safety risk, is time consuming, and increases effluent generation. In this study, inorganic 3D heteroborane cluster strong acids are employed for the first time as homogeneous catalysts. Three novel isomeric tetrachlorido and tetrabromido derivatives of 3,3 '-commo-bis[undecahydrido-closo-1,2-dicarba-3-cobaltadodecaborate](1-) [1-] were synthesised and fully characterised using a range of analytical techniques, including NMR, TLC, HPLC, MS, UV-Vis, melting point (MP), CHN analyses, and XRD. Ultimately, H3O[8,8 '-Cl2-1-] was identified as the most efficient, reusable, and non-corrosive homogeneous catalyst for the esterification of four fatty acids. The reactions are conducted in an excess of alcohol at reflux. The effective absorption of water vapour provided by the molecular sieves maximises acid conversion. The hydrophobic dye Sudan black B was employed as an acid-base indicator to facilitate a comparison of the H0 acidity function of sulphuric acid and halogenated heteroboranoic acids when dissolved together in methanol. The 23Na NMR analysis demonstrated that the application of dry methanol resulted in the displacement of Na+ ions from zeolite, which subsequently exchanged the H3O+ ions of the acid. This process led to a gradual reduction in the efficiency of the catalysts, particularly with repeated use. The solution to this issue is to regenerate the catalyst on the ion exchanger following each reaction. In contrast to the published methods, our new approach meets 10 of 12 green chemistry principles.

A Sonogashira coupling of meta-iodocalix[4]arene with various terminal acetylenes confirmed that the meta position of calixarene is well addressable, and that both thermal and microwave protocols led to good yields of alkynylcalixarenes. Alkynes thus obtained were subjected to the ferric chloride and diphenyl diselenide-promoted electrophilic closure. It turns out that the calix[4]arenes give completely different bridging products than those described for the non-macrocyclic starting compounds. This can be demonstrated not only by the isolation of products with a six-membered ring (6-exo-dig), but mainly by the smooth formation of the 5-endo-dig cyclization, which has never been observed in the aliphatic series. An attempt at electrocyclization led to a high yield of the 1,2-diketone (oxidation of the starting alkyne), again in contrast to the reaction described for the acyclic derivatives. The structures of the unexpected products were unequivocally established by X-ray analysis and clearly demonstrate how the preorganized macrocyclic skeleton favors a completely different regioselectivity of cyclization reactions compared to common aliphatic compounds.

A starting thiacalix[4]arene can be easily transformed into oxidized phenoxathiin-based macrocycles 9 and 9', representing an unusual structural motif in calixarene chemistry. The presence of electron-withdrawing groups (SO2, SO) and the considerable internal strain caused by the condensed heterocyclic moiety render these molecules susceptible to nucleophilic attack. The reaction with various organolithium reagents provides a number of different products resulting from the cleavage of either the calixarene skeleton or the phenoxathiin group or both ways simultaneously. This enables the preparation of thiacalixarene analogues with unusual structural features, including systems containing a biphenyl fragment as a part of the macrocyclic skeleton. The above-described transformations, unparalleled in classical calixarene chemistry, clearly demonstrate the synthetic potential of this thiacalixarene subgroup.

Apremilast (APR) is an anti-inflammatory drug commonly used in the treatment of psoriasis. In efforts to enhance its solubility, several cocrystals with similar structural features have been developed. This study investigates the cocrystallization of APR with four phenolic-type coformers: phenol, catechol, pyrogallol, and hydroxyquinol. These coformers differ in the number and position of their hydroxyl groups, with their melting points varying by as much as 100 °C. Four novel cocrystal forms were synthesized, purified, and characterized using X-Ray diffraction and thermal analysis techniques. Surprisingly, the resulting cocrystals exhibited minimal differences in their melting points. The molecular packing of APR appears to limit the network-forming potential of the hydroxyl groups, a conclusion supported by the solved crystal structures, Hirshfeld surface analysis, and differential scanning calorimetry (DSC) results.

This study investigates the hydrogen-bond geometry in six two-component solid systems composed of quinoline and chloro-nitrobenzoic acids. New X-ray diffraction studies were conducted using both the conventional independent-atom model and the more recent Hirshfeld atom-refinement method, with the latter providing precise hydrogen-atom positions. The systems can be divided into salts (the hydrogen atom transferred to the quinoline nitrogen), cocrystals (the hydrogen atom retained by the acid), and intermediate structures. Solid-state NMR experiments corroborated the X-ray diffraction-derived H-N distances. DFT calculations, using five functionals including hybrid B3LYP and PBE0, showed varying energy profiles for the hydrogen bonds, with notable differences across functionals. These calculations revealed different preferences for salt or cocrystal structures, depending on the functional used. Path-integral molecular dynamics simulations incorporating nuclear quantum effects demonstrated significant hydrogen-atom delocalization, forming a hydrogen-bond continuum, and provided average N-H distances in excellent agreement with experimental results. This comprehensive experimental and theoretical approach highlights the complexity of multicomponent solids. The study emphasizes that the classification into salts or cocrystals is frequently inadequate, as the hydrogen atom is often significantly delocalized in the hydrogen bond. This insight is crucial for understanding and predicting the behavior of such systems in pharmaceutical applications.

Fluorination reactivity and selectivity of TBAT and four new nucleophilic fluorination reagents were better than those of TBAF, TASF and other quaternary ammonium fluorides.

Nucleophilic fluorination of secondary aliphatic substrates, especially of halides, still remains a challenge. Among the available reagents, TBAT belongs to one of the best choices due to its stability, affordable price and low toxicity. With the aim to improve its selectivity, we synthesized three analogues modified in the aryl part of the TBAT reagent with one or two electron donating methoxy groups or with one electron withdrawing trifluoromethyl group. All three reagents are air-stable compounds and their structure was confirmed by a single crystal X-ray analysis. In testing the reactivity and selectivity of the reagents with a library of secondary bromides, as well as of other selected primary and secondary substrates, we found that substitution with methoxy groups mostly improves both reactivity and selectivity compared to TBAT, while the substitution with trifluoromethyl group leads to inferior results. Difluorosilicates modified by more than two electron donating methoxy groups proved to be unstable and decomposed spontaneously to the HF2- anion. DFT calculations of tetramethylammonium analogues of the studied reagents disclosed that the substitution of the phenyl group with the methoxy substituent lowers the transitions state energy of the decomposition to a fluorosilane-fluoride complex, while the substitution with the trifluoromethyl group has an opposite effect. Difluorosilicates with MeO group(s) gave improved nucleophilic fluorination activity and selectivity of secondary substrates, while the CF3 group gave inferior results.

Pillar[n]arenes are among the newest members of the macrocyclic family. Nevertheless, their conformational behavior and binding properties as well as redox properties of dealkylated pillar[n]arenes are well-studied. At the same time, introducing a heteroatom into a cyclophane macrocycle is already known to alter all the above properties drastically. This study presents a simple synthetic approach based on thia-Michael addition cyclization that readily resulted into hexathiapillar[6]arene with four phenylene units alternated by two redox-active hydroquinone moieties. The straightforward synthesis of the macrocycle enabled a systematic study of its conformation and redox behavior. The modification of hexathiapillar[6]arene afforded five functionalized derivatives, which were studied structurally in detail. The findings revealed interesting redox and structural properties of the macrocycle and its derivatives including the formation of crystal lattices with continuous channels and empty voids.

As the first known example of ring-opening cross metathesis (ROCM) of polyfluorinated strained cyclobutenes, ROCM of 3,3,4,4-tetrafluorocyclobutene with electronically rich alkenes, catalyzed by Grubbs or Hoveyda-Grubbs 2nd generation precatalysts, gave a small library of non-symmetrical isolated dienes bearing a tetrafluoroethylene spacer between the double bonds. 1-Butoxy-3,3,4,4-tetrafluorohexa-1,5-diene thus formed underwent subsequent regioselective cross metathesis (CM) with a series of styrenes, catalyzed by Hoveyda-Grubbs 2nd generation precatalyst, leading to non-symmetrically substituted dienes. 6,6-Dibutoxy-3,3,4,4-tetrafluorohex-1-ene, formed by regioselective butoxylation of 1-butoxy-3,3,4,4-tetrafluorohexa-1,5-diene, was dihydroxylated and cyclized to the corresponding 3,3,4,4-tetrafluorohexopyranose.