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A series of ammonium salts was used to propose a step-by-step approach to obtain the stabilization energy and contact area data of supramolecular clusters in charged molecules. A new parameter was presented to assess the cluster energy efficiency.

Crystallization mechanisms were proposed to investigate hydrogen bond and aromatic donor–acceptor interactions in a series of phenyl–perfluorophenyl amides. The modulation of NH⋯OC bonds and aryl complementarity drove a new cocrystal growth.

Quantitative similarity indices (IX) were combined with crystallization mechanism proposals to shed more light on the origins of the supramolecular similarity between a series of benzimidazole derivative structures.

This paper covers the synthesis of a series of eleven examples of new 7-(1H-pyrrol-1-yl)spiro[chromeno[4,3-b]quinoline-6,1′-cycloalkanes] (3), where cycloalkanes are cyclopentane, cyclohexane, and cycloheptane. Heterocyclic system 3 was successfully obtained in 53–78% yields by the Clauson–Kaas reaction, in which 7-amino-spiro[chromeno[4,3-b]quinoline-6,1′-cycloalkanes] (1) were reacted with 2,5-dimethoxytetrahydrofuran (2) in an acetic acid medium at 90 °C for 48 h. Then, to demonstrate synthetic applicability, the 9-bromoquinoline-substituted derivative 3h was selected and successfully employed in traditional CC and CN cross-coupling reactions, yielding three new modified tacrine scaffolds (4–6). Photophysical studies of π → π* and n → π* transitions corroborated the aromatic structures of the heterocycle molecules and showed high emission properties, good Φf values, and moderate to large Stokes shifts (SS).

The crystallization mechanisms of a series of fourteen 7-chloro-4-substituted-quinolines (substituents: (1) OCH3, (2) OCH2CH3, (3) OCH2CHCH2, (4) O(CH2)2OH, (5) O(CH2)3OH, (6) NH(CH2)2CH3, (7) NH(CH2)3CH3, (8) NH(CH2)2OH, (9) NHCH(CH2CH3)CH2OH, (10) NH(CH2)2Cl, (11) NHNCH(C6H5), (12) NHNCH(2-FC6H4), (13) NHNCH(3-FC6H4), and (14) NHNCH(4-FC6H4)) were proposed based on a retrocrystallization approach using the supramolecular cluster as demarcation. Crystallization mechanism stage parameters – NCG% and NG/NC – were determined. The 4-substituents present in quinolines caused six different mechanisms, starting from the monomers in solution to dimers, 1D nuclei, and 2D nuclei (6, 11, 12); 2D nucleus formation (5); 1D nuclei to 2D nuclei (7, 9); concomitant dimers and 1D nuclei to a 3D crystal (8); 1D nuclei directly to a 3D crystal lattice (1–4, 10, 14), and dimers to 2D nuclei and then to a 3D crystal (13). Analysis of GAI showed atom⋯atom intermolecular interactions in the proposed first nuclei for compounds 4 and 5. The nucleation process inferred in the solid state was partially confirmed during the formation of the proto-crystal in solution due to the changes of the hydrogen chemical shift in variable-concentration 1H-NMR experiments. Results revealed that the size of the alkyl chain and the presence of different functional groups in the 4-substituents influenced the crystallization process.

The synthesis and structural elucidation of a new series of six 6-amino-2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl) quinolines are reported, yielding 22 to 87% isolated products. This was achieved through a regioselective intramolecular cyclization reaction of novel (Z)-4-((4-aminophenyl)amino)-1,1,1-trifluoro-but-3-en-2-ones in an acidic solvent-free medium, in which alkyl/aryl/heteroaryl = methyl, phenyl, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl. The novel compounds were fully characterized by 1H-, 13C- and 19F-NMR spectroscopy, GC-MS and single-crystal X-ray diffraction. In addition, the preliminary investigation of photophysical properties of the 6-aminoquinolines (UV-Vis, fluorescence, quantum yield calculations, Stokes shifts, and TD-DFT analysis) and inhibitory activity against M. tuberculosis H37Rv strain was also presented. Thermal analyses were carried out to assess their properties as new materials.

Deep eutectic solvents (DES) have been used as sustainable media for the synthesis of more efficient nanoparticle-based catalysts. However, the effects of DES deposition on the catalytic activity of metal oxide nanoparticles like TiO2 are unknown. Thus, the goal of this study was to facilitate the deposition of DES onto TiO2 surfaces and investigate how this coating modulates the catalytic activity of TiO2 in the photodecomposition of organic dyes. Results for the thermal and spectroscopic properties of the TiO2 coated with DES in relation to pure materials indicated interactions between these two materials, confirming the deposition of DES onto the TiO2 surface. Different choline chloride : HBD molar ratios had little impact on the thermal stability, phase transitions, crystallization and amorphization of the mixture. In general, the catalytic activity of TiO2 coated with DES was reduced. However, TiO2 covered with ChCl : malonic acid (1 : 2) showed the best catalytic activity and it was better as greater the amount of DES used in the surface deposition.

Reaction of 5-bromo enones with pyrazoles provided a series of unexpected N,O-aminal derivatives, through a 1,4-conjugated addition at the β-carbon of the 5-bromo enones instead of the expected nucleophilic substitution of the bromine. This reaction also furnished the 1,3-regioisomer of the pyrazole. A similar reaction of pyrazoles using 5-bromo enaminones furnished only N-alkylated pyrazoles-with high regioselectivity and at good yields-through nucleophilic substitution of the bromine.

This work reports a successful synthesis of two new series of 2-(aryl/heteroaryl)-6-(morpholin-4-yl/pyrrolidin-1-yl)-(4-trifluoromethyl)quinolines via the Buchwald–Hartwig amination, at 60–88% yields, starting from 2-(aryl/heteroaryl)-6-bromo-4-trifluoromethyl-quinolines and heteroarylamines (morpholine and pyrrolidine). The 6-bromoquinoline precursors were obtained from an easy intramolecular cyclization reaction of (Z)-4-((4-bromophenyl)amino)-1,1,1-trifluoro-but-3-en-2-ones, which were previously prepared through the reaction of 4-methoxy-(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones with 4-bromoaniline. Photophysical analyses indicated intraligand and charge-transfer type transitions, in agreement with the aromatic structures of the heterocycle moieties. In the case of ct-DNA titrations (via the absorption and emission method), morpholinyl- and pyrrolydinyl-substituted quinolines had strong interactions with ct-DNA, which could be attributed to π-stacking and/or hydrogen-bonding interactions.

A series of 5(3)-aryl-3(5)-carboxyethyl-1-tert-butylpyrazoles (aryl, 4-X-C6H4, where X = H, F, Cl and Br) were studied in the solid state. The 1,3-regioisomers (carboxyethyl group in 3-position) of t-butylpyrazoles crystalized in three different forms: s-cis, s-trans or s-cis + s-trans. On the other hand, the 1,5-regioisomers (carboxyethyl group in 5-position) of t-butylpyrazoles showed only s-trans conformation. The 13C CPMAS and SCXRD data confirmed that each 1,3- and 1,5-regioisomers of t-butylpyrazoles crystallized only one of the three mentioned forms. The potential energy surface (PES) yielded insights regarding the formation of each conformer. In general, quantum mechanical calculations showed that the conformer s-trans is more stable than s-cis, and the calculated stability difference was 0.7 kcal mol−1 for the 1,3-regioisomers and 3.5 kcal mol−1 for the 1,5-regioisomers. Moreover, 1,5-regioisomers of t-butylpyrazoles showed intramolecular interactions of type CH⋯OC between the carbonyl and t-butyl group, which was obtained by QTAIM analysis. This interaction can influence the stabilization for s-trans conformation in the solid state. In contrast, the 1,3-regioisomers did not show intramolecular interaction with the COOEt group, and the conformation adopted in the solid state should be the consequence of the crystalline packing. The QTAIM analysis of the more stable dimers of s-trans-conformation for X = Cl, Br showed that the halogen atoms interact with the COOEt group, helping stabilize this conformation. On the other hand, in the s-cis⋯s-cis conformation dimer (X = Cl, Br), the COOEt group was stabilized by the phenyl group, which is the same stabilization for X = H.

This paper presents a series of six examples of 1,1-difluoro-3-aryl(heteroaryl)-1H-pyrido[1,2-c][1,3,5,2]oxadiazaborinin-9-ium-1-uides (2)—in which aryl(heteroaryl) = phenyl, 4-MeC6H4, 4-N(CH3)2C6H4, 4-NO2C6H4, 2-naphthyl, and 2-thienyl—as pyridine-based boron heterocycles with variable ligand structures. The heterocycles 2 were easily synthesized at yields of 51–70% from reactions—at room temperature for 24 h—of simple N-(pyridin-2-yl)benzamides (1) with BF3·Et2O, and they were fully characterized by 1H-, 13C-, 19F-, and 11B-NMR spectroscopy, GC-MS, and X-ray diffractometry. The optical and electrochemical properties of 2 (UV-vis spectra, fluorescence spectra, quantum yield calculations, Stokes’ shifts, redox potentials, and DFT calculations) were determined and discussed. BSA-binding experiments and molecular docking studies of new complexes 2 were performed and correlated between each other.

The nickel-catalyzed cyclization of in situ generated ortho-chlorobenzophenone hydrazone derivatives, to afford 3-(hetero)aryl-1H-indazoles, is documented for the first time. The product 1H-indazoles can be transformed subsequently in a one-pot procedure into 1,3-di(hetero)aryl-1H-indazoles via copper-catalyzed N-arylation with (hetero)aryl bromides.

This work reports a successful one-pot three-step protocol for the synthesis of a new series of 15 examples of polysubstituted 4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazoles, in which sequential Sonogashira cross-coupling, desilylation, and a copper(I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC) with an overall yield of up to 72% were used. The presence of a trifluoromethyl substituent attached to the pyrazole moiety made the Sonogashira cross-coupling reaction challenging. Additionally, the selection of the ancillary ligand XPhos was essential and indispensable for the desired heterocyclic construction.

The synthesis of benzylic amide [2]rotaxanes using 1,2-bis(aminocarbonyl-(1′-tert-butyl-1H-pyrazole-[3′]5′-yl))-ethanes as templates is reported. These templates are equipped with tert-butyl pyrazole-based stoppers and have donor (N–H) and acceptor (CO) hydrogen bond groups. The synthesis of [2]rotaxanes has been shown to be highly dependent on the tert-butylpyrazole stoppers. While the thread with 1′,3′-disubstituted pyrazoles as stopper units was shown to be an excellent template for the synthesis of [2]rotaxanes, the thread with 1′,5′-disubstituted pyrazoles as stopper units did not yield the expected [2]rotaxane. The structure of the synthesized [2]rotaxanes was characterized using NMR experiments and X-ray diffraction, with the latter showing that the macrocycle adopts a distorted chair conformation. An in-depth study of the isolated thread's X-ray structures and concentration-dependent NMR experiments seem to explain the dependence of the rotaxane formation on the substitution pattern of the thread's pyrazole stoppers.

A mild and efficient protocol for the assembly of tetra-substituted 5-trifluoromethylpyrazoles is presented, involving halogenation at the 4-position of readily prepared tri-substituted 5-trifluoromethylpyrazoles to give 4-halo-1-phenyl-5-trifluoromethyl pyrazoles, and subsequent palladium-catalyzed Negishi or Buchwald-Hartwig cross-couplings to install carbon or nitrogen-based 4-substituents. Key to the success of these challenging cross-couplings is the use of XPhos and JosiPhos CyPF-tBu ligands, respectively.

The synthesis, crystallization, and theoretical calculations (energetic dimers and QTAIM analyses) of three polymorphs of 3,12-dihydrotetrabenzo[d,h,m,q]-[1–3, 10–12]hexaazacyclooctadeca-1,10-dien-5,14-diyne are reported. The supramolecular cluster approach is proposed for understanding the formation and stabilization of crystal arrangements of the polymorphs. The results show that the π⋯π-interactions were responsible for the crystal packing of the three polymorphs and that they are in a determined energetic region. The energetic difference between the more stable and less stable polymorphs is around 8 kcal mol−1, indicating that if, probably other polymorphs will be formed, all of them will be in the same energetic region. The results confirmed that the first molecular coordination sphere (supramolecular cluster) is the smallest portion of the crystal that represents all necessary energy information for understanding the intermolecular interactions in the entire crystal.

A simple procedure to obtain 4-acyl-1-substituted-1,2,3-triazoles, using a deep eutectic solvent (DES), ChCl and ethylene glycol at a 1 : 2 ratio, as the reaction medium is described. The products were obtained in high selectivity and good yields (70–84%). The advantages of the method include easy work-up, metal-free conditions, inexpensiveness, and the ability to be used four times without a loss in yield.

The supramolecular structure of 3-amino-4-halo-5-methylisoxazoles (halo = Cl, Br, and I) was investigated in order to suggest a route for crystallization of small molecules. The hierarchy of intermolecular interactions during the growth of the crystal was established by X-ray diffraction, 1H NMR titration, QTAIM analysis and quantum mechanical calculations. The relationship between QTAIM and energetic data was the fundamental innovation in this work. It allowed partitioning of the dimer interaction energy between interacting atoms. The partitioning shows the cooperation of the intermolecular interactions in the stabilization of the dimers and led to observation of the energetic consequences that small changes in the molecular structure of each compound may have on the crystal packing. The proposed route for the crystallization of the supramolecular cluster was based on the energetic hierarchy, in which the hydrogen bond is the strongest interaction and the first to form, and the π-interactions are weaker than the hydrogen bond and cannot compete with it. However, the π-interactions are responsible for the growth of the crystal, connecting the rising layers of the hydrogen bond dimers. The other interaction formed, the halogen bond, is too weak to compete with the other two interactions, but it is fundamental for linking the layer that leads to the final three-dimensional arrangement. Finally, a new way of understanding the crystallization process and the design of new materials is presented.

In this work, an approach is proposed for understanding the crystal arrangements of organic compounds. The crystals are studied taking into account the stabilization energy and the topological properties like contact surfaces of a molecule (M1) due to the presence of neighboring Mn (cluster). The molecular system models chosen were five heterocycles and one β-enaminone. The cluster of compounds had a Molecular Coordination Number (MCN) of 14, except for one compound that had an MCN of 16. Our study showed that intermolecular interactions can be divided into four main types: type I, with large energy values and a small contact surface; type II, involving a large value for both the energy and the contact surface; type III, with small and medium energy values, and a medium-sized contact surface; and type IV, with small energy values and a relatively large contact surface. Additionally, from this approach we show that only from the supramolecular cluster is it possible to observe the participation of the topological component during the formation of the crystal. This is demonstrated by the fact that the fragility of the electrostatic interaction between M1 and one Mn in the same plane is compensated by a strong interaction of M1 with a molecule in another plane.