Heibbe C. B. de Oliveira

The Biginelli Reaction with an Imidazolium–Tagged Recyclable Iron Catalyst: Kinetics, Mechanism, and Antitumoral Activity

The present work describes the synthesis, characterization, and application of a new ion-tagged iron catalyst. The catalyst was employed in the Biginelli reaction with impressive performance. High yields have been achieved when the reaction was carried out in imidazolium-based ionic liquids (BMI⋅PF6, BMI⋅NTf2, and BMI⋅BF4), thus showing that the ionic-liquid effects play a role in the reaction. Moreover, the ion-tagged catalyst could be recovered and reused up to eight times without any noticeable loss in activity. Mechanistic studies performed by using high-resolution electrospray-ionization quadrupole-time-of-flight mass (HR-EI-QTOF) spectrometry and kinetic experiments indicate only one reaction pathway and rule out the other two possibilities under the development conditions. The theoretical calculations are in accordance with the proposed mechanism of action of the iron catalyst. Finally, the 37 dihydropyrimidinone derivatives, products of the Biginelli reaction, had their cytotoxicity evaluated in assays against MCF-7 cancer cell linages with encouraging results of some derivatives, which were virtually non-toxic against healthy cell linages (fibroblasts).

Mechanistic Studies on Lewis Acid Catalyzed Biginelli Reactions in Ionic Liquids: Evidence for the Reactive Intermediates and the Role of the Reagents

This paper describes the use of common Lewis acids supported in imidazolium-based ionic liquids as the catalysts to promote the Biginelli reaction. The ionic liquid effect and the reaction mechanism are discussed on the basis of nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI-MS), and theoretical calculations. Indeed, the results showed that the ionic medium plays a fundamental role in the synthesis of biologically active dihydropyrimidinones due to the stabilization of the charged intermediates proposed in the mechanism. When conducted in an ionic liquid as solvent, the reaction mechanism is more complex than in other Lewis acid catalyzed Biginelli reactions.

Synthesis, properties and highly selective mitochondria staining with novel, stable and superior benzothiadiazole fluorescent probes

The present manuscript describes the synthesis of two novel 2,1,3-benzothiadiazole (BTD) derivatives containing an excited state intramolecular proton transfer (ESIPT) site. Photophysical properties, X-ray analysis, ESIPT and intramolecular charge-transfer (ICT) of these novel fluorescent monosubstituted BTD derivatives were investigated. It is also shown that ESIPT and ICT can take place concomitantly. Theoretical calculations (ab initio and DFT) corroborate the high stability of these derivatives in the excited state due to efficient ESIPT and ICT processes. Also, the optimized calculated geometries of these new structures allowed a better understanding of the different behaviour of the dyes in a wide pH range (1–13). Finally, the new compounds exhibit impressive cellular selectivity and stain only mitochondria in different cell lines and are far better than the commercially available MitoTracker-red.

Morita–Baylis–Hillman Reaction: ESI-MS(/MS) Investigation with Charge Tags and Ionic Liquid Effect Origin Revealed by DFT Calculations

The use of a charge-tagged acrylate derivative bearing an imidazolium tag to study the Morita-Baylis-Hillman reaction via ESI-MS(/MS) monitoring and the effect of such tag (imidazolium cations and ion pairs) over TSs is described. The ionic nature of the substrate was meant to facilitate ESI transfer to the gas phase for direct mass spectrometric analysis. The detection and characterization of charged intermediates has suggested major reaction pathways. DFT calculations considering the effect of a polar and protic solvent (methanol), of a polar and aprotic solvent (acetonitrile), and of no solvent (gas phase) were used to predict possible TSs through a common accepted intermediate. The controversial proton transfer step, which may proceed via Aggarwals or McQuades proposals, was evaluated. Calculations predicted the formation of electrostatic intermediate complexes with both the cation and anion when charge-tagged reagents are used. These complexes contribute to the positive ionic liquid effect, and based on the formation of these unique complexes, a rationale for the ionic liquid effect is proposed. These complexes also pointed to a plausible explanation for the positive ionic liquid effect observed in several reactions that are difficult to be carried out in organic solvents but have shown a beneficial effect when performed in ionic liquids.

Selective and efficient mitochondrial staining with designed 2,1,3-benzothiadiazole derivatives as live cell fluorescence imaging probes

Novel designed 2,1,3-benzothiadiazole fluorescent probes were synthesized, characterized and applied as live cell fluorescence imaging probe staining only mitochondria in mammalian cancer cell lines (MCF-7). The efficiency of these new probes was found to be much superior to that of the commercially available MitoTracker® Red. Cellular and in vitro experiments allowed better understanding of the relationship between the planned molecular architecture of the new dyes and the observed cellular selectivity.

Phosphine-free Heck reaction: mechanistic insights and catalysis “on water” using a charge-tagged palladium complex

A novel Pd-complex with a charge tag (imidazolium cation) was applied for online monitoring of the neutral Heck reaction by electrospray ionization (tandem) mass spectrometry – ESI-MS(/MS). The results shed light on the mechanism of the reaction, whereas the charge-tagged ligand also allowed the unprecedented MS monitoring of Pd2+ reduction to Pd0. Key reaction intermediates associated with Pd catalysis could also be detected and characterized due to the presence of the charge tag on the Pd-complex. DFT calculations supported the proposed mechanism. The new charge-tagged Pd-complex is also shown to function as an active catalyst “on water” with the advantage of using cheaper and less reactive aryl chloride substrates in a phosphine-free version of the Heck reaction.

Designed Benzothiadiazole Fluorophores for Selective Mitochondrial Imaging and Dynamics

A series of new rationale designed 2,1,3-benzothiadiazole (BTD) fluorescent derivatives has been synthesized and applied for cellular selective staining of cancer cells in cell-imaging experiments. Four new synthesized BTD derivatives showed only poor or reasonable cellular selection, but with excellent fluorescence intensity and almost no background signal emitting at the blue or green channels. The knowledge gained by analysing their molecular architecture, however, allowed the planning and synthesis of a fluorescent BTD, which was then successfully tested and showed superior mitochondrial selection with outstanding results in bioimaging experiments in living cells. The new marker (named Splendor) was then compared with the commercially available MitoTracker Red (also through co-staining experiments) and showed far better mitochondrial selection, fluorescence intensity and chemical stability. Mitochondrial imaging and tracking (dynamic changes) was possible using Splendor during the whole cellular division cycle. DFT calculations were performed to offer insights into the origin of the chemical- and photostability of BTD derivatives. In addition, molecular docking calculations hint at a potential molecular target for the BTD derivatives in the mitochondrial protein adenine nucleotide translocase, which may explain the mitochondrial selectivity of Splendor versus the other four BTD derivatives.

Condensed, solution and gas phase behaviour of mono- and dinuclear 2,6-diacetylpyridine (dap) hydrazone copper complexes probed by X-ray, mass spectrometry and theoretical calculations

We describe the synthesis of novel mononuclear and dinuclear copper complexes and an investigation of their behaviour in solution using mass spectrometry (ESI-MS and ESI-MS/MS) and in the solid state using X-ray crystallography. The complexes were synthesized from two widely used diacetylpryridine (dap) ligands, i.e. 2,6-diacetylpyridinebis(benzoic acid hydrazone) and 2,6-diacetylpyridinebis(2-aminobenzoic acid hydrazone). Theoretical calculations (DFT) were used to predict the complex geometries of these new structures, their equilibrium in solution and energies associated with the transformations.

Deformed transition-state theory: Deviation from Arrhenius behavior and application to bimolecular hydrogen transfer reaction rates in the tunneling regime

A formulation is presented for the application of tools from quantum chemistry and transition‐state theory to phenomenologically cover cases where reaction rates deviate from Arrhenius law at low temperatures. A parameter d is introduced to describe the deviation for the systems from reaching the thermodynamic limit and is identified as the linearizing coefficient in the dependence of the inverse activation energy with inverse temperature. Its physical meaning is given and when deviation can be ascribed to quantum mechanical tunneling its value is calculated explicitly. Here, a new derivation is given of the previously established relationship of the parameter d with features of the barrier in the potential energy surface. The proposed variant of transition state theory permits comparison with experiments and tests against alternative formulations. Prescriptions are provided and implemented to three hydrogen transfer reactions: CH4 + OH → CH3 + H2O, CH3Cl + OH → CH2Cl + H2O and H2 + CN → H + HCN, widely investigated both experimentally and theoretically.

Bioimaging, cellular uptake and dynamics in living cells of a lipophilic fluorescent benzothiadiazole at low temperature (4 °C)

A novel lipophilic fluorescent small-molecule 2,1,3-benzothiadiazole derivative (named here as BTD-AO) was designed, synthesized, characterized and applied as a live cell-imaging probe. Its cellular uptake and cellular dynamics at low temperature (4 °C) using MDA-MB-237 were investigated. Confocal bioimages revealed that the new bioprobe was capable of easily transposing the cell-membrane at low temperatures and also revealed the dynamics of BTD-AO over time. BTD-AO had a high affinity for vesicles (lipid droplets) and had its subcellular location precisely determined during its migration in the cells.