Clarissa P. Frizzo

Ionic Liquids in Heterocyclic Synthesis

2.5. Ionic Liquids Presented in This Review 2020 3. Cyclocondensation Reactions 2020 4. Synthesis of Three-Membered Heterocycles 2022 4.1. Aziridines 2022 5. Synthesis of Five-Membered Heterocycles 2022 5.1. Pyrroles 2022 5.2. Furans 2022 5.3. Thiophenes 2023 5.4. Pyrazoles 2024 5.5. Imidazoles 2025 5.6. Isoxazoles 2027 5.7. Oxazoles, Oxazolines, and Oxazolidinones 2027 5.8. Thiazoles and Thiazolidinones 2028 6. Synthesis of Six-Membered Heterocycles 2030 6.1. Pyridines 2030 6.2. Quinolines 2031 6.3. Acridines 2033 6.4. Pyrans 2033 6.5. Flavones 2035 6.6. Pyrimidines and Pyrimidinones 2035 6.7. Quinazolines 2037 6.8. -Carbolines 2038 6.9. Dioxanes 2039 6.10. Oxazines 2039 6.11. Benzothiazines 2040 6.12. Triazines 2040 7. Synthesis of Seven-Membered Heterocycles: Diazepines 2041

Solvent-Free Heterocyclic Synthesis

6.1. Oxadiazoles 4154 6.2. Diazaphospholes 4154 7. Six-Membered Heterocycles with One Heteroatom 4155 7.1. Pyridines 4155 7.2. Pyridinones 4155 7.3. Quinolines 4156 7.4. Quinolinones 4157 7.5. Isoquinolines 4157 7.6. Acridines 4158 7.7. Pyranones 4158 7.8. Flavones 4159 8. Six-Membered Heterocycles with Two Heteroatoms 4159 8.1. Pyridazinones 4159 8.2. Pyrimidines 4159 8.3. Pyrimidinones 4160 8.4. Quinazolines 4162 8.5. Quinazolinones 4162 8.6. Quinoxalines 4164 8.7. Quinoxalinediones 4165 8.8. Oxazines 4165 8.9. Oxazinones 4166 8.10. Thiazines 4166 9. Six-Membered Heterocycles with Three Heteroatoms 4166

Aromaticity in heterocycles: new HOMA index parametrization

A new parametrization for the Harmonic Oscillator Model of Aromaticity (HOMA) index to determine aromaticity of heterocycles is introduced. The new HOMA for Heterocycle Electron Delocalization (HOMHED) is based on the experimental data from electron diffraction X-ray for the reference molecules used to estimate the simple, double, and optimal bond lengths. Bond length of “pure” single and double bonds of non-conjugated systems or systems without π-electrons and/or n-electron delocalization were considered. The HOMHED index was determined for a series of five and six heterocycles with C–C, C–N, C–O, C–S, N–N, N–O, and N–S bonds. The π-electron delocalization of these heterocycles was determined by Krygowski-reformulated HOMA and HOMHED and it was proved that HOMHED worked in line with HOMA for all heterocycles, except those containing oxygen, which were found to be weak aromatic from Krygowski rHOMA calculations.Graphical AbstractThe correlationship between Krygowski-reformulated HOMA (rHOMA) and a new parametrized model (HOMHED) for heterocyles is performed. It was proved that HOMHED worked in line with HOMA for all heterocycles, except those containing oxygen, which were found to be weak aromatic from rHOMA calculations.

Preparation of TiO2 Nanoparticles Coated with Ionic Liquids: A Supramolecular Approach

Coated TiO2 nanoparticles by dicationic imidazolium-based ionic liquids (ILs) were prepared and studied by differential scanning calorimetry (DSC), dynamic light scattering (DLS), transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and scanning electron microscopy (SEM). Three ILs with different hydrophobicity degrees and structural characteristics were used (IL-1, IL-2, and IL-3). The interaction between IL molecules and the TiO2 surface was analyzed in both solid state and in solution. The physical and chemical properties of coated nanoparticles (TiO2 + IL-1, TiO2 + IL-2, and TiO2 + IL-3) were compared to pure materials (TiO2, IL-1, IL-2, and IL-3) in order to evaluate the interaction between both components. Thermal behavior, diffraction pattern, and morphologic characteristics were evaluated in the solid state. It was observed that all mixtures (TiO2 + IL) showed different behavior from that detected for pure substances, which is an evidence of film formation. DLS experiments were conducted to determine film thickness on the TiO2 surface comparing the size (hydrodynamic radius, Rh) of pure TiO2 with coated nanoparticles (TiO2 + IL). Results showed the thickness of the film increased with hydrophobicity of the IL compound. TEM images support this observation. Finally, X-ray diffraction patterns showed that, in coated samples, no structural changes in TiO2 diffraction peaks were observed, which is related to the maintenance of the crystalline structure. On the contrary, ILs showed different diffraction patterns, which confirms the hypothesis of interactions happening between IL and the TiO2 nanoparticles surface.

Dicationic imidazolium-based ionic liquids: a new strategy for non-toxic and antimicrobial materials

New dicationic imidazolium-based ionic liquids (ILs) were synthesized, characterized and tested in regards to cytotoxicity and antimicrobial activity. Insertion of a new cationic head and use of organic anions increased the biocompatibility of the ILs developed. IC50 (concentration necessary to inhibit 50% of enzymatic activity) values obtained were considerably higher than those described for monocationic ILs, which indicates an improvement in cytocompatibility. Antimicrobial activity against bacterial species of clinical relevance in wounds and the oral environment was tested. The results showed that ILs were effective in inhibiting bacterial growth even below the minimum inhibitory concentration (MIC). It was observed that structural features that confer higher hydrophobicity to ILs decreased both the IC50 and MIC simultaneously. However, it was possible to establish an equilibrium between those two effects, which gives the safe range of concentrations that ILs can be employed. The results demonstrated that the dicationic-imidazolium-based ILs synthesized may constitute a potent strategy for applications requiring non-toxic materials exhibiting antimicrobial activity.

2-methyl-7-substituted pyrazolo[1,5-a]pyrimidines: highly regioselective synthesis and bromination

The reaction of 3-amino-5-methyl-1H-pyrazole with 1,1,1-trichloro-4-alkoxy-3-alken-2-ones [CCl3C(O)CH=C(R1)OR, where R1/R = H/Me, Me/Et, Et/Me, Pr/Et, Bu/Me, iso-Bu/Me] or β-dimethylaminovinyl ketones [R2C(O)CH=CHNMe2, where R2 = Ph, Ph-4-Me, Ph-4-F, Ph-4-Cl, Ph-4-Br, Ph-4-NO2, fur-2-yl, thien-2-yl, pyrrol-2-yl, pyrid-2-yl], in acetic acid under reflux for 16 hours, furnished highly regioselective the halomethylated pyrazolo[1,5-a]pyrimidines and aryl[heteroaryl]pyrazolo[1,5-a]pyrimidines, respectively. A protocol for the bromination reaction at the 3-position pyrazolo[1,5-a]pyrimidines also was investigated.

Reaction of β-alkoxyvinyl halomethyl ketones with cyanoacetohydrazide

The synthesis of thirteen 1-cyanoacetyl-5-hydroxy-5-halomethyl-1H-4,5-dihydropyrazoles from the reaction of 4-alkoxy-3-alken-2-ones [R3C(O)C(R2)=C(R1)(OR), where R3 = CF3, CCl3, CHCl2, CO2Et; R2 = H, Me; R1 = H, Me, Et, Pr, Pentyl, c-Hexyl, Ph, and R = Me, Et] with cyanoacetohydrazide is reported. In order to show the versatility of using the 1-cyanoacetyl-substituted pyrazoles as important building blocks in organic synthesis, some attempts to obtain pyrazole derivatives also are described.

Energetic and topological insights into the supramolecular structure of dicationic ionic liquids

The crystal structures of dicationic ILs [DBMIM][2BF4] (1) and [DBMIM][2Br]·[2H2O] (2) were investigated in order to explore the intermolecular interactions in these compounds. An energetic and topological approach for characterization of supramolecular clusters in organic crystals was used. The study of the crystals was done by considering the stabilization energy and topological properties such as contact surfaces and energy content between cations and neighboring anions (supramolecular clusters). The study showed that: 1 is auto-organized into layers (one-dimensional structure) by an anion–cation interaction (weak electrostatic and ionic), and the three-dimensional supramolecular structure of 2 is constructed through simultaneous interactions between cations, anions, and water molecules. This network results in interaction chains in two different directions. Additionally, the supramolecular cluster approach allowed evaluation of the participation of the topological component during the formation of the crystals of 1 and 2. Among the different types of interactions proposed, the most predominant was the one classified as type III, which has small and medium energy values, and a medium-sized contact surface. The thermal and morphological properties were also studied to further characterize these materials and to better understand the resulting structure–property relationships.

Pyrazole synthesis under microwave irradiation and solvent-free conditions

This paper presents a study of solvent-free reaction conditions using microwave irradiation (MW) to obtain 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles by the cyclocondensation reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C(R1)OR, where R/R1 = Et/H, Me/Me and Me/Ph] with hydrazines [NH2NH-R2, where R2 = CO2Me, Ph, CH2CH2OH]. Some reactions were performed under the same reaction conditions using methanol as solvent. The results obtained using MW equipment for synthesis under solvent-free conditions were also compared with those described in literature for conventional thermal heating and heating with a domestic MW oven. In general, the products furnished by reaction in MW equipment for synthesis presented better yields and shorter reaction times. In addition, it was demonstrated that the reaction temperature altered the formation of products for each hydrazine showing that MW equipment for synthesis is efficient for reacting hydrazines and 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones to procedure the products 4,5-dihydro-1H-pyrazoles and dehydrated pyrazoles.

Proposal for crystallization of 3-amino-4-halo-5-methylisoxazoles: an energetic and topological approach

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.