Photo-activated Carbon dots (CDs) as Catalysts in the Knoevenagel Condensation: A Mechanistic Study by Dual-Mode Monitoring via ESI-MS.

Carbon dots (CDs) obtained from 5-(hydroxymethyl)furfural (5-HMF) were activated by a 365 nm-UV irradiation source and employed in the Knoevenagel condensation to investigate their photocatalytic mechanism. To this end, electrospray ionization mass spectrometry (ESI-MS) was used to monitor the time progress of the condensation and follow the formation of the final product in positive and negative ion modes at once. The intervention of the superoxide radical anion in the photocatalytic mechanism of CDs was highlighted.

Free N-heterocyclic carbenes from Brønsted acidic ionic liquids: Direct detection by electrospray ionization mass spectrometry.

RATIONALE: The occurrence of N-heterocyclic carbenes in imidazolium-based ionic liquids has long been discussed, but no spectroscopic evidence has been reported yet due to their transient nature. The insertion of an ionizable acid group into the cation scaffold of an ionic liquid which acts as a charge tag allows for the direct detection of free carbenes by mass spectrometry. METHODS: Three different Brønsted acidic ionic liquids were synthesized: 1-methyl-3-carboxymethylimidazolium chloride (MAICl), 1-methyl-3-carboxymethylimidazolium acetate (MAIAc) and the corresponding 2-(3-methyl-1H-imidazol-3-ium-1-yl)acetate zwitterion (MAI - H). The speciation of these compounds was then analysed by electrospray ionization ion-trap mass spectrometry in the negative ion mode. RESULTS: The C2-H deprotonation of the imidazolium cation leading to the formation of the corresponding carbene is highly affected by the basic properties of the counter-anion. In the case of MAICl and MAI - H ionic liquids, no charged species corresponding to the free N-heterocyclic carbene was detected. On the contrary, in the presence of a sufficiently basic anion, such as acetate of MAIAc ionic liquid, an intense signal related to the free carbenic species was observed without the addition of an external base. CONCLUSIONS: In situ formation of free N-heterocyclic carbenes from Brønsted acidic ionic liquids was demonstrated, highlighting the crucial role of anion basicity in promoting the C2-H proton abstraction from imidazolium cations with a carboxylic side chain.

Charge-Tagged N-Heterocyclic Carbenes (NHCs): Revealing the Hidden Side of NHC-Catalysed Reactions through Electrospray Ionization Mass Spectrometry.

N-heterocyclic carbenes (NHCs) are key intermediates in a variety of chemical reactions. Owing to their transient nature, the interception and characterization of these reactive species have always been challenging. Similarly, the study of reaction mechanisms in which carbenes act as catalysts is still an active research field. This Minireview describes the contribution of electrospray ionization mass spectrometry (ESI-MS) to the detection of charge-tagged NHCs resulting from the insertion of an ionic group into the molecular scaffold. The use of different mass spectrometric techniques, combined with the charge-tagging strategy, allowed clarification of the involvement of NHCs in archetypal reactions and the study of their intrinsic chemistry.

New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation.

In order to obtain multi-functional molecules for Alzheimer's disease, a series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathology. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain molecules potentially able to chelate bio-metals colocalized in Aß plaques and involved in the generation of radical species. Synthesized compounds were tested by enzymatic inhibition studies towards EeAChE and eqBChE using Ellman's method. The most potent EeAChE inhibitor is compound 5a, with a Ki of 788 ± 51 nM, while the most potent eqBChE inhibitors are compounds 12 and 19, with Ki values of 182 ± 18 nM and 258 ± 25 nM respectively. Selected compounds, among the most potent cholinesterases inhibitors, were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma).

Graphene Oxide: A Smart (Starting) Material for Natural Methylxanthines Adsorption and Detection.

Natural methylxanthines, caffeine, theophylline and theobromine, are widespread biologically active alkaloids in human nutrition, found mainly in beverages (coffee, tea, cocoa, energy drinks, etc.). Their detection is thus of extreme importance, and many studies are devoted to this topic. During the last decade, graphene oxide (GO) and reduced graphene oxide (RGO) gained popularity as constituents of sensors (chemical, electrochemical and biosensors) for methylxanthines. The main advantages of GO and RGO with respect to graphene are the easiness and cheapness of synthesis, the notable higher solubility in polar solvents (water, among others), and the higher reactivity towards these targets (mainly due to - interactions); one of the main disadvantages is the lower electrical conductivity, especially when using them in electrochemical sensors. Nonetheless, their use in sensors is becoming more and more common, with the obtainment of very good results in terms of selectivity and sensitivity (up to 5.4 × 10-10 mol L-1 and 1.8 × 10-9 mol L-1 for caffeine and theophylline, respectively). Moreover, the ability of GO to protect DNA and RNA from enzymatic digestion renders it one of the best candidates for biosensors based on these nucleic acids. This is an up-to-date review of the use of GO and RGO in sensors.

The Electrogenerated Cyanomethyl Anion: An Old Base Still Smart.

The cathodic reduction of acetonitrile solutions containing a tetraalkylammonium salt leads to the formation of the cyanomethyl anion (-CH2CN, cyanomethanide). This electrolysis can be carried out under very simple experimental conditions (constant-current electrolyses), using various cathodic materials, controlling the amount of base by simply controlling the amount of charge. Despite the fact that the mechanism for this electrochemical reaction is still debated (and it depends on the cathodic material), the outcome of the electrolysis is the formation of a strong base, -CH2CN (pKa 31.3 for acetonitrile in DMSO). The chemical behavior of this electrogenerated base (EGB) strongly depends on its counterion, which in this case is a tetraalkylammonium cation, with a low charge density and thus not coordinated. The very weak interaction between R4N+ and -CH2CN renders the cyanomethyl anion a "naked" ion, and thus highly reactive. In particular, the cyanomethyl anion can react as a base and as a nucleophile. In the first case, it behaves as a strong base and, after deprotonation of a weak acidic substrate, transforms itself into a solvent molecule, acetonitrile, thus generating no byproducts. In the second case, the reactivity as a nucleophile of the cyanomethyl anion obviously depends on the reaction partner. When an electrophile is present in the reaction mixture, a cyanomethylation is obtained (e.g., with aromatic aldehydes, possessing no acidic hydrogen atoms, which undergo nucleophilic attack on the carbonyl carbon atom by -CH2CN); on the contrary, when no reagent is present other than acetonitrile and tetraalkylammonium salt, an attack on the parent molecule leads to the acetonitrile dimer, 3-aminocrotononitrile, which in turn can behave as a base and/or as a nucleophile. In this regard, some authors report that it is preferable to carry out the electrogeneration of the cyanomethyl anion under different experimental conditions, i.e., using an undivided cell and a sacrificial magnesium anode. In this way, a Grignard-type reagent is formed (Mg(CH2CN)2) which highly stabilizes the cyanomethyl anion, preventing its dimerization. It should be noted that in our laboratory the electrogenerated tetraalkylammonium cyanomethanide was extensively used in various reactions (both acid-base and nucleophile-electrophile, vide infra), and in almost no case, the amount of acetonitrile dimer formed exceeded 5%, confirming the validity of this electrochemical methodology to generate a very efficient base. Moreover, when in the reaction mixture both a weak acid and an electrophile are present, the prevalent reactivity of the cyanomethyl anion is as a base, leaving the possibility of a cyanomethylation reaction to those cases in which no acidic substrate is present. We have successfully used the electrogenerated cyanomethyl anion in many base-induced reactions, as the synthesis of the ß-lactam ring (chiral or not), the insertion of carbon dioxide into amines and amino alcohols, the activation of elemental sulfur and insertion into carbonyl compounds, the selective alkylation of difunctional compounds, etc.

NHC in Imidazolium Acetate Ionic Liquids: Actual or Potential Presence?

Ionic liquids (ILs) are considered in the majority of cases green solvents, due to their virtually null vapor pressure and to the easiness in recycling them. In particular, imidazolium ILs are widely used in many fields of Chemistry, as solvents or precursors of N-heterocyclic carbenes (NHCs). The latter are easily obtained by deprotonation of the C2-H, usually using strong bases or cathodic reduction. Nevertheless, it is known that weaker bases (e.g., triethylamine) are able to promote C2-H/D exchange. From this perspective, the possibility of deprotonating C2-H group of an imidazolium cation by means of a basic counter-ion was seriously considered and led to the synthesis of imidazolium ILs spontaneously containing NHCs. The most famous of this class of ILs are N,N'-disubstituted imidazolium acetates. Due to the particular reactivity of this kind of ILs, they were appointed as "organocatalytic ionic liquids" or "proto-carbenes." Many papers report the use of these imidazolium acetates in organocatalytic reactions (i. e., catalyzed by NHC) or in stoichiometric NHC reactions (e.g., with elemental sulfur to yield the corresponding imidazole-2-thiones). Nevertheless, the actual presence of NHC in N,N'-disubstituted imidazolium acetate is still controversial. Moreover, theoretical studies seem to rule out the presence of NHC in such a polar environment as an IL. Aim of this Mini Review is to give the reader an up-to-date overview on the actual or potential presence of NHC in such an "organocatalytic ionic liquid," both from the experimental and theoretical point of view, without the intent to be exhaustive on N,N'-disubstituted imidazolium acetate applications.

Electrochemically modified Corey-Fuchs reaction for the synthesis of arylalkynes. The case of 2-(2,2-dibromovinyl)naphthalene.

The electrochemical reduction of 2-(2,2-dibromovinyl)naphthalene in a DMF solution (Pt cathode) yields selectively 2-ethynylnaphthalene or 2-(bromoethynyl)naphthalene in high yields, depending on the electrolysis conditions. In particular, by simply changing the working potential and the supporting electrolyte, the reaction can be directed towards the synthesis of the terminal alkyne (Et4NBF4) or the bromoalkyne (NaClO4). This study allowed to establish that 2-(bromoethynyl)naphthalene can be converted into 2-ethynylnaphthalene by cathodic reduction.

New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation.

A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 µM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.

Characterization of naproxen-polymer conjugates for drug-delivery.

The synthesis and the characterization of three new naproxen decorated polymers are described. A versatile and general approach is employed to link the drug to polymers, affording the derivatives with a very high degree of purity. The release of the drug from the conjugates proved to be exceptionally slow, even in acidic aqueous media, and the kinetic of the process seems to be triggered by their solubility in water. On the other hand, the interesting outcome of the first ex vivo drug release experiments on human blood samples makes this preliminary study valuable for future investigations on the use of these polymeric prodrugs in in vivo treatment of inflammatory states.

Efficient electrochemical N-alkylation of N-boc-protected 4-aminopyridines: towards new biologically active compounds.

The use of electrogenerated acetonitrile anion allows the alkylation of N-Boc-4-aminopyridine in very high yields, under mild conditions and without by-products. The high reactivity of this base is due to its large tetraethylammonium counterion, which leaves the acetonitrile anion "naked." The deprotection of the obtained compounds led to high yields in N-alkylated 4-aminopyridines. Nonsymmetrically dialkylated 4-aminopyridines were obtained by subsequent reaction of monoalkylated ones with t-BuOK and alkyl halides, while symmetrically dialkylated 4-aminopyridines were obtained by direct reaction of 4-aminopyridine with an excess of t-BuOK and alkyl halides. Some mono- and dialkyl-4-aminopyridines were selected to evaluate antifungal and antiprotozoal activity; the dialkylated 4-aminopyridines 3ac, 3ae and 3ff showed antifungal towards Cryptococcus neoformans; whereas 3cc, 3ee and 3ff showed antiprotozoal activity towards Leishmania infantum and Plasmodium falciparum.

Umpolung reactions in an ionic liquid catalyzed by electrogenerated N-heterocyclic carbenes. Synthesis of saturated esters from activated α,ß-unsaturated aldehydes.

The umpolung reaction of α,ß-unsaturated aldehydes to saturated esters has been carried out in an ionic liquid by organocatalysis of electrogenerated NHC. The roles of solvent, precatalyst and proton donor of the ionic liquid have been verified and good to high yields of esters have been obtained using a "green" and mild methodology.

Electrogenerated NHC as an organocatalyst in the Staudinger reaction.

Electrogenerated N-heterocyclic carbene can behave as an organocatalyst in the Staudinger reaction (from imine and acyl chloride) in a very polar solvent, such as an ionic liquid.

Selective and environmentally friendly methodologies based on the use of electrochemistry for fine chemical preparation: an efficient synthesis of N,N'-disubstituted ureas.

A novel efficient synthesis of N,N'-disubstituted ureas has been developed. Aromatic and aliphatic primary amines undergo oxidative carbonylation under atmospheric pressure of carbon monoxide using Pd(II) catalyst in combination with its anodic recycling at a graphite electrode.