Marco Lombardo

A recyclable triethylammonium ion-tagged diphenylphosphine palladium complex for the Suzuki–Miyaura reaction in ionic liquids

Suzuki-Miyaura reactions of aryl bromides and arylboronic acids proceed in good to excellent yields in a pyrrolidinium ionic liquid by using a preformed air stable and easily handled triethylammonium-tagged diphenylphosphine palladium(II) complex (2). The reaction requires short reaction times and mild temperature conditions and does not show any tendency towards the formation of palladium black. After extraction of the product, the catalyst containing ionic liquid phase is easily recycled for 6 times, with no significant loss of catalytic activity.

Ionic Tags in Catalyst Optimization: Beyond Catalyst Recycling

In the pursuit of sustainability and efficiency in catalysis, the recourse to liquid–liquid biphasic homogeneous conditions is rapidly growing. In this context, the efficient entrapment of a catalyst in a solvent such as water or an ionic liquid can be achieved by installing an ionic substituent on the catalyst structure, the so called ion‐tag strategy. Little attention has been devoted in the literature to the fact that ion tags often improve catalytic performances compared to the parent tag‐free catalyst. From statistical scrutiny of literature data, a working hypothesis has been developed as a basis for further investigation and testing; a decrease of the free‐energy barrier is frequently observed as the result of an interplay of coulombic and steric interactions between developing charges in a polar transition state and the tag’s ion pair. If this is true, a way to develop more efficient catalytic protocols will entail a rational installation of an ionic group onto the structure of a known catalyst, complying with simple empirical guidelines that are discussed herein.

A Liquid–Liquid Biphasic Homogeneous Organocatalytic Aldol Protocol Based on the Use of a Silica Gel Bound Multilayered Ionic Liquid Phase

An innovative two stage liquid–liquid biphasic homogeneous protocol for the asymmetric organocatalytic aldol reaction is proposed, based on the use of the cis‐ion‐tagged proline 8 dissolved in the liquid film of a multilayered ionic liquid covalently bonded to silica gel 4. The resulting catalytically active material 9 is first soaked with cyclohexanone in the presence of water, resulting in a semi‐transparent gel, then the aldehyde is added and the mixture stirred at RT. In the first stage, 4 acts as a catalyst reservoir that delivers 8 to the cyclohexanone phase allowing the reaction to take place homogeneously. In the second stage, cyclohexanone is removed under vacuum and the resulting slurry is extracted with anhydrous diethylether. Now 4 acts as a catalyst sponge, redissolving 8. Product extraction is extremely selective; no trace of catalyst is detected in the product‐containing phase, and 9 can be easily reused several times with high cumulative productivity values (up to 523).

Organocatalytic conjugate addition of nitroalkanes to 3-ylidene oxindoles: a stereocontrolled diversity oriented route to oxindole derivatives.

An efficient and highly enantioselective Michael addition of nitroalkanes to 3-ylidene oxindoles is described, mediated by thiourea-based bifunctional organocatalysts. The stereochemistry at C(α) and C(β) centers is perfectly controlled, and the intermediate C-3 enolate is trapped with a second Michael acceptor. The developed one-pot three-component consecutive reactions generate up to four contiguous stereocenters, including the C-3 all-carbon quaternary center, in a perfectly defined configuration. The conversion of the β-nitro oxindole into the corresponding β-amino derivative discloses synthetically useful transformations, exploitable to generate pharmaceutically attractive molecular targets.

Microwave Assisted Synthesis of a Small Library of Substituted N,N′-Bis((8-hydroxy-7-quinolinyl)methyl)-1,10-diaza-18-crown-6 Ethers

N,N-bis-((8-hydroxy-7-quinolinyl)methyl)-1,10-diaza-18-crown-6 ether 1a and its analogue 1c are known as fluorescent sensors of magnesium in living cells. With the aim to investigate the effects of the substitution pattern on the photophysical properties of ligands 1 and their metal complexes, we developed an efficient microwaves enhanced one-pot Mannich reaction to double-armed diaza-crown ligands 1 carrying a variety of substituents. This new protocol is characterized by shorter reaction times, enhanced yields, and improved product purities with respect to the use of conventional conductive heating.

Diaza-18-crown-6 hydroxyquinoline derivatives as flexible tools for the assessment and imaging of total intracellular magnesium

Although magnesium is essential for a number of biological processes crucial for cell life, its distribution and intracellular compartmentalization have not been thoroughly elucidated yet, mainly because of the inadequacy of the available techniques to map intracellular magnesium distribution. For this reason, particular interest has been recently raised by a family of fluorescent molecules, diaza-18-crown-6 8-hydroxyquinolines (DCHQ1 and its derivatives), that show a remarkable affinity and specificity for magnesium, higher than all the commercially available probes, thus permitting the detection of the total intracellular magnesium. A recently optimized synthetic approach to DCHQ using microwave heating allowed us to easily generate a variety of substituted DCHQ derivatives with improved fluorescence, uptake and selective localization with respect to the original reference material (DCHQ1). The introduction of aromatic side groups enhanced the fluorescence response in cells and also improved intracellular uptake and retention of the probes even after washing. Enhanced uptake has also been achieved with an acetoxymethyl ester derivative that is recognized by the intracellular esterases. Finally, the insertion of two long hydrophobic side chains allowed a better staining of the membranes due to the high affinity to the lipophilic environment. These results show the potential of these new fluorescent probes as effective tools for shedding light on total intracellular magnesium distribution and homeostasis.

Quantitative chemical imaging of the intracellular spatial distribution of fundamental elements and light metals in single cells.

We report a method that allows a complete quantitative characterization of whole single cells, assessing the total amount of carbon, nitrogen, oxygen, sodium, and magnesium and providing submicrometer maps of element molar concentration, cell density, mass, and volume. This approach allows quantifying elements down to 10(6) atoms/μm(3). This result was obtained by applying a multimodal fusion approach that combines synchrotron radiation microscopy techniques with off-line atomic force microscopy. The method proposed permits us to find the element concentration in addition to the mass fraction and provides a deeper and more complete knowledge of cell composition. We performed measurements on LoVo human colon cancer cells sensitive (LoVo-S) and resistant (LoVo-R) to doxorubicin. The comparison of LoVo-S and LoVo-R revealed different patterns in the maps of Mg concentration with higher values within the nucleus in LoVo-R and in the perinuclear region in LoVo-S cells. This feature was not so evident for the other elements, suggesting that Mg compartmentalization could be a significant trait of the drug-resistant cells.

Dioxetane-doped silica nanoparticles as ultrasensitive reagentless thermochemiluminescent labels for bioanalytics.

Thermochemiluminescence (TCL; the light emission originating by the thermally triggered decomposition of a molecule) was proposed in the late 1980s as a detection technique for immunoassays. However, after little pioneering work, this technique was abandoned because of the high temperatures required and the poor detectability in comparison to other labels. Here we describe for the first time a thermochemiluminescent acridine-based 1,2-dioxetane with a remarkably low (i.e., below 100 °C) emission-triggering temperature, which made it possible to obtain light emission even in an aqueous environment, as well as amino-functionalized silica nanoparticles loaded with this compound and the fluorescent energy acceptor dipyridamole. Thanks to the signal amplification due to the large number of 1,2-dioxetane molecules in each nanoparticle (about 10(4)) and the increased emission efficiency due to energy transfer to the fluorescent acceptor, the doped nanoparticles could be revealed with a detectability close to that of chemiluminescent enzyme labels (the limit of detection of doped nanoparticles by TCL imaging was 1 × 10(-16) mol mm(-2), thus approaching the value of 5 × 10(-17) mol mm(-2) obtained for the enzyme label horseradish peroxidase with chemiluminescence detection). They could thus be used as highly detectable labels in the development of sensitive TCL-based immunoassays and nucleic acid hybridization assays, in which the detection step does not require any additional chemical reagent. We believe that these doped silica nanoparticles could pave the way for the revival of TCL detection in bioanalytics, taking advantage of the reagentless detection and the high signal/noise ratio in comparison with conventional luminescence detection techniques.

A new class of antimalarial dioxanes obtained through a simple two-step synthetic approach: rational design and structure-activity relationship studies.

A new series of simple endoperoxides, characterized by a 3-methoxy-1,2-dioxane scaffold, was designed on the basis of a previously developed pharmacophore. Through a simplified and versatile scheme of synthesis, which utilizes cheap and commercially available starting materials, it was possible to obtain several structurally and stereochemically different compounds that were tested against P. falciparum. Most of compounds showed antimalarial activity in the low micromolar range and no cellular toxicity, all being significantly more active on chloroquine resistant (CQ-R) than on chloroquine sensitive (CQ-S) strains. Resulting structure-activity relationships were analyzed by means of experimental and computational techniques, validating our design rationale and tailoring it for the new scaffold. Our study demonstrated that according to the hypothesized mechanism of action, the antimalarial activity can be improved through rational structural modifications, paving the way for the development of new simplified antimalarial endoperoxides.

Preparation and characterization of thermochemiluminescent acridine-containing 1,2-dioxetanes as promising ultrasensitive labels in bioanalysis.

Thermochemiluminescence is the luminescence process in which a thermodynamically unstable molecule decomposes with light emission when heated above a threshold temperature. We recently reported the thermochemiluminescence properties of an acridine-containing 1,2-dioxetane, which emits at relatively low temperatures (i.e., below 100 °C). Herein, we explored the effect of the introduction of methyl substituents in the acridine system. The methyl group did not determine an excessive destabilization of 1,2-dioxetane ring nor significantly affect the general physical properties of the molecule. Monosubstituted methyl derivatives and a series of derivatives bearing several combinations of two, three, and four methyl groups were prepared. The rate of formation of 1,2-dioxetane derivatives 1b-k strongly depended on the methyl substitution pattern. All members of this library of mono-, di-, tri-, and tetramethyl-substituted derivatives were characterized in terms of photophysical and thermochemiluminescence properties. The introduction of methyl groups into the acridine ring caused a marked decrease in the activation energy of the thermochemiluminescent reaction. Tri- and tetramethyl-substituted acridones had the highest fluorescence quantum yields, in the range 0.48-0.52, and the corresponding 1,2-dioxetanes 1h and 1j showed in thermochemiluminescence imaging experiments limit of detection values more than ten times lower with respect to the unsubstituted derivative.