Dipolar Aprotic Media Research Articles

Waste minimized one-pot synthesis of azido- or triazole-pyrazolines using polarclean as reaction medium

Herein, we report a sustainable, atom and step-efficient protocol for the one-pot preparation of azido and triazole-functionalized pyrazoline employing a non-toxic, biodegradable, and industrial production waste-derived Polarclean:H2O (4:1) mixture as safer dipolar aprotic reaction medium. The cyclization and di-functionalization of N-tosyl β,γ-unsaturated hydrazones in the presence of a cost-effective CuSO4 catalyst and NaN3 results in high-yield formation of azido-functionalized pyrazolines, easily isolated through simple filtration. The introduction of an azido group to the pyrazoline scaffold allows for the design of a mild, atom-economical one-pot multi-step procedure for the synthesis of triazole-decorated pyrazolines that were isolated in high yield and purity (up to 99%) through straightforward filtration. Both the CuSO4 catalyst and the Polarclean:H2O (4:1) medium proved to be optimal for promoting the one pot Cu(II) cyclization/azidation of β,γ-unsaturated hydrazones in the presence of K2S2O8 as oxidant and then, without isolating the azido-derivative intermediates, the Cu(I) azido-alkynes cyclization by simply adding a stoichiometric amount of an alkyne and 10 mol% of a biocompatible reductant, such as sodium ascorbate. The current protocol, characterized by mild reaction conditions and simple products isolation, shows above all low E-factor values and exceptional Environmental and Safety Hazard Scores (ES and SHZS), confirming its overall sustainability and benignity.

Effects of Light Energy and Reducing Agents on C60‐Mediated Photosensitizing Reactions

Many biomolecules contain photoactive reducing agents, such as reduced nicotinamide adenine dinucleotide (NADH) and 6-thioguanine (6-TG) incorporated into DNA through drug metabolism. These reducing agents may produce reactive oxygen species under UVA irradiation or act as electron donors in various media. The interactions of C60 fullerenes with biological reductants and light energy, especially via the Type-I electron-transfer mechanism, are not fully understood although these factors are often involved in toxicity assessments. The two reductants employed in this work were NADH for aqueous solutions and 6-TG for organic solvents. Using steady-state photolysis and electrochemical techniques, we showed that under visible light irradiation, the presence of reducing agents enhanced C60 -mediated Type-I reactions that generate superoxide anion (O2(.-)) at the expense of singlet oxygen ((1)O2) production. The quantum yield of O2(.-) production upon visible light irradiation of C60 is estimated below 0.2 in dipolar aprotic media, indicating that the majority of triplet C60 deactivate via Type-II pathway. Upon UVA irradiation, however, both C60 and NADH undergo photochemical reactions to produce O2(.-), which could lead to a possible synergistic toxicity effects. C60 photosensitization via Type-I pathway is not observed in the absence of reducing agents.

Hydrogen‐bonded nucleophile effects in ANS: the reactions of 1‐chloro and 1‐fluoro‐2,4‐dinitrobenzene with 2‐guanidinobenzimidazole, 1‐(2‐aminoethyl)piperidine andN‐(3‐aminopropyl)morpholine in aprotic solvents

AbstractThe kinetics of the reactions of 2,4‐dinitrofluorobenzene (DNFB) and 2,4‐dinitrochlorobenzene (DNClB) with 2‐guanidinobenzimidazole (2‐GB) at 40 ± 0.2 °C in dimethylsulphoxide (DMSO), toluene, and in toluene–DMSO mixtures, and with 1‐(2‐aminoethyl)piperidine (2‐AEPip) andN‐(3‐aminopropyl)morpholine (3‐APMo) in toluene at 25 ± 0.2 °C were studied under pseudo first‐order conditions. For the reactions of 2‐GB carried out in pure DMSO, the second‐order rate coefficients were independent of the amine concentration. In contrast, the reactions of 2‐GB with DNFB in toluene, showed a kinetic behaviour consistent with a base‐catalysed decomposition of the zwitterionic intermediate. These results suggest an intramolecular H‐bonding of 2‐GB in toluene, which is not present in DMSO. To confirm this interpretation the reactions were studied in DMSO–toluene mixtures. Small amounts of DMSO produce significant increase in rate that is not expected on the basis of the classical effect of a dipolar aprotic medium; the effect is consistent with the formation of a nucleophile/co‐solventmixed aggregate. For the reactions of 3‐APMo with both substrates in toluene, the second‐order rate coefficients,kA, show a linear dependence on the [amine]. 3‐APMo is able to form a six‐membered ring by an intramolecular H‐bond which prevents the formation of self‐aggregates. In contrast, a third order was observed in the reactions with 2‐AEPip: these results can be interpreted as a H‐bonded homo‐aggregate of the amine acting as a better nucleophile than the monomer. Most of these results can be well explained within the frame of the ‘dimer nucleophile’ mechanism. Copyright © 2010 John Wiley & Sons, Ltd.

A new calix[4]arene derivative and its ionic recognition for silver(i) and mercury(ii): the solvent effect

A new lower rim partially functionalized calix[4]arene, namely, 5,11,17,23-tetra-tert-butyl[25,27-bis(diethylthiocarbamoyl)oxy]calix[4]arene, 1 was synthesized and characterized by 1H NMR in different deuterated solvents to assess the degree of solvent–ligand interactions and the conformation of 1 in solution. 1H NMR, conductometric and thermodynamic investigations reveal that this receptor interacts only with silver(I) and mercury(II) in dipolar aprotic media. The complexation process has been thermodynamically characterized and the results are compared with the corresponding data (when available) involving analogous ligands and these metal cations in the appropriate solvent. Emphasis is made on the difference between ‘selective extraction’ and ‘selective ionic recognition’ by receptors. Final conclusions are given.

Calix[4]Pyrrole Derivative: Recognition of Fluoride and Mercury Ions and Extracting Properties of the Receptor-Based New Material

A calix[4]pyrrole derivative, namely, meso-tetramethyl tetrakis (4-phenoxy methyl ketone) calix[4]pyrrole, 1, was synthesized and structurally (1H NMR) and thermodynamically characterized. The complexing properties of this receptor with a wide variety of anions and cations in dipolar aprotic media (acetonitrile, propylene carbonate, and dimethyl sulfoxide) were investigated through 1H NMR and conductance studies. The former technique was used to assess whether or not complexation occurs and if so to identify the active sites of interaction of 1 with ions. The composition of the complexes was established by conductance measurements. It was found that in dipolar aprotic solvents, 1 interacts only with two polluting ions (fluoride and mercury). The complexation thermodynamics of 1 and these ions in these solvents is reported. The medium effect on the binding process involving the fluoride ion is discussed taking into account the solvation properties of reactants and the product. Complexes of moderate stability are found. Given that this is an important factor to consider for the recycling of the loaded material in extraction processes, 1 was treated with formaldehyde in basic medium leading to the production of a calix[4]pyrrole based material able to extract fluoride and mercury (II) ions from water. Thus the optimum conditions for the extraction of these ions from aqueous solutions were established. The material is easily recyclable using an organic acid. Final conclusions are given.

Inverse Solvent Effects in Carbocation Carbanion Combination Reactions: The Unique Behavior of Trifluoromethylsulfonyl Stabilized Carbanions

Second-order rate constants for the reactions of the trifluoromethylsulfonyl substituted benzyl anions 1a-e (CF3SO2CH(-)-C6H4-X) with the benzhydrylium ions 2f-j and structurally related quinone methides 2a-e have been determined by UV-vis spectroscopy. The reactions proceed approximately 10-40 times faster in methanol than in DMSO leading to the unique situation that these carbocation carbanion combinations are faster in protic than in dipolar aprotic media. The pK(a) values of some benzyl trifluoromethylsulfones were determined in methanol (1c-H, 17.1; 1d-H, 16.0; 1e-H, 15.0) and found to be 5 units larger than the corresponding values in DMSO. Rate and equilibrium measurements thus agree that the trifluoromethylsulfonyl substituted benzyl anions 1a-e are more effectively solvated by ion-dipole interactions in DMSO than by hydrogen bonding in methanol. Brønsted correlations show that in DMSO the trifluoromethylsulfonyl substituted carbanions 1 are less nucleophilic than most other types of carbanions of similar basicity, indicating that in DMSO the intrinsic barriers for the reactions of the localized carbanions 1 are higher than those of delocalized carbanions, including nitroalkyl anions. The situation is reversed in methanol, where the reactions of the localized carbanions 1 possess lower intrinsic barriers than those of delocalized carbanions as commonly found for proton-transfer processes. As a consequence, the relative magnitudes of intrinsic barriers are strongly dependent on the solvent.

Cation/Anion Recognition by A Partially Substituted Lower Rim Calix[4]arene Hydroxyamide, A Ditopic Receptor

The complexation ability of a partially substituted lower rim calix[4]arene hydroxyamide derivative, 25,27-bis[N-(2-hydroxy-1,1-bishydroxymethylethyl)amino- carbonylmethoxy]calix[4]arene-26,28-diol, 1, for cations and anions was investigated through (1)H NMR, conductometry, spectrophotometry, and calorimetry in dipolar aprotic media. (1)H NMR studies of 1 in the deuterated solvents (acetonitrile, methanol, and dimethylsulfoxide) reflect ligand-solvent interactions in methanol and dimethylsulfoxide. As far as the cations are concerned, a selectivity peak is found when standard Gibbs energies of complexation of 1 with cations (alkaline-earth, zinc, and lead) are plotted against corresponding data for cation hydration. This finding reflects the key role played by the desolvation and binding processes in the overall complexation of this receptor and these cations in acetonitrile. This is also interpreted in terms of enthalpy and entropy data. Factors such as, the nature and the arrangement of donor atoms in the hydrophilic cavity of the ligand on cation complexation process, are discussed. This paper also addresses anion complexation processes. It is found that 1 interacts through hydrogen bond formation with fluoride, dihydrogen phosphate, and pyrophosphate in acetonitrile and N,N-dimethylformamide. The thermodynamics associated with these processes is fully discussed taking into account literature data involving calix[4]pyrroles and these anions in these solvents. Previous work regarding the water solubility of these ligands is discussed. It is concluded that 1 behaves as a ditopic ligand in dipolar aprotic media.

Anion Complexation by Calix[3]thieno[1]pyrrole: The Medium Effect

The interaction of calix[3]thieno[1]pyrrole, 1, and halide and dihydrogen phosphate anions in a variety of solvents (acetonitrile, propylene carbonate, N,N-dimethylformamide, and dimethyl sulfoxide) has been investigated through 1H NMR, conductance measurements, and titration calorimetry. 1H NMR measurements reveal the sites of interaction of the ligand with the anions in CD3CN while the composition of the complex was determined through conductance measurements. A quantitative assessment of anion-ligand interactions is provided. Thus the thermodynamics of complexation of 1 with halide and dihydrogen phosphate anions in dipolar aprotic media at 298.15 K is reported. These data are interpreted in terms of the thermodynamics of transfer of reactants and product from a reference solvent (acetonitrile) to other solvents. The crucial role played by the solvent on the ability of the ligand to interact with anions and on the composition of the complex is demonstrated.

Double-Cavity Calix[4]pyrrole Derivative with Enhanced Capacity for the Fluoride Anion

A double-cavity calix[4]pyrrole derivative, meso-tetramethyl-tetra[N-(2-phenoxyethyl)-N'-phenylurea]calix[4]pyrrole, 1, with enhanced hosting ability for the fluoride anion has been designed and characterized. Its interaction with anions (fluoride, chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulfate, perchlorate, nitrate, and trifluoromethane sulfonate) was qualitatively and quantitatively assessed through 1H NMR, conductance, and calorimetric studies. The outcome of these investigations demonstrates that 1 interacts only with fluoride and dihydrogen phosphate anions in dipolar aprotic media. However, the composition of these complexes differs in that two units of fluoride are taken per unit of 1, while a 1:1 anion/ligand complex is formed with the dihydrogen phosphate anion. Results from the 1H NMR studies are striking in that these not only provide information about the active sites of the ligand-anion interaction but also allow the establishment of the sequence of events taking place during fluoride complexation. Thus, hydrogen-bond formation between the pyrrolic hydrogen and the fluoride anion is followed by the uptake of a second anion through the same type of interaction, but with the phenyl urea. It is also the latter group that is responsible for the interaction of 1 with the dihydrogen phosphate anion. Finally, this paper illustrates the importance of structural information for the interpretation of the thermodynamics associated with these systems.

Hydrocarbobutoxylation of Phenylacetylene on Palladium Complexes: A Solvent Effect

Data on changes in the activity of the Pd(dba)2/2TsOH/10Ph3P (dba is dibenzylideneacetone) and PdCl2(Ph3P)2/8Ph3P catalytic systems in the reaction of phenylacetylene with CO and n-butanol under the action of a solvent (aromatic hydrocarbons, chloroalkanes, ethers, esters, ketones, and dipolar aprotic media) are presented. The differences found in the response of either of the systems to changes in the properties of the medium are discussed in terms of a scheme of the catalytic cycle of reaction. It is noted that activity does not correlate with the physicochemical characteristics (polarity, basicity, and electron-acceptor ability) of solvents.

Complexation of Calix[4]arene Derivatives and Trivalent Cations in Dipolar Aprotic Media

The complexation of p-tert-butylcalix[4]arene tetraethanoate, 1a, p-tert-butylcalix[4]arene tetramethyl ketone, 1b, and p-tert-butylcalix[4]arene tetraacetamide, 1c, and trivalent cations was investigated in acetonitrile and N,N-dimethylformamide at 298.15 K using several techniques. 1H NMR measurements in CD3CN at 298 K were carried out for the systems involving 1a, 1b, and 1c as ligands and Sc3+, Y3+, Eu3+, and Yb3+ as cations. For the latter ligand, 1H NMR titration with La3+ was also carried out to assess the sites of interaction of these ligands and the appropriate cation in this solvent. Conductance measurements were performed in acetonitrile and N,N-dimethylformamide with the aim of determining the composition of the metal ion complexes. Stability constants and derived standard Gibbs energies, enthalpies, and entropies reveal that, as far as 1b is concerned, this ligand is not able to distinguish among the trivalent cations as a result of a remarkable enthalpy−entropy compensation effect. This is not the case for 1c and these cations in acetonitrile and to a lesser extent in N,N-dimethylformamide. The selective behavior of this ligand for these metal cations is reflected in the stability constants, which are higher in acetonitrile than in N,N-dimethylformamide. A plot of log Ks values against the cation radius shows a “selectivity” peak. In acetonitrile, the complex stability is greater than that previously observed for an analogous derivative and these cations in this solvent. The medium effect on the complexation process is discussed.

Synthetic Applications of Dealkoxycarbonylations of Malonate Esters, β-Keto Esters, α-Cyano Esters and Related Compounds in Dipolar Aprotic Media - Part II

Synthetic Applications of Dealkoxycarbonylations of Malonate Esters, β-Keto Esters, α-Cyano Esters and Related Compounds in Dipolar Aprotic Media - Part II

Removal of ethoxycarbonyl groups from polymer-supported esters

Polymer-supported C,C-dialkylated malonates were deethoxycarbonylated quantitatively by inorganic salts applied in dipolar aprotic medium. Changes of the reagent excess, temperature, quality of the reagent as well as of the solvent were tested. Effect of the temperature was found as decisive: unusual low (100°C) temperature resulted in complete transformations. The advantages of deethoxycarbonylation in polymer-supported synthesis were evaluated comparing it to the traditional reaction sequence (hydrolysis+decarboxylation). Polymer-supported substrates were directly tested by IR spectrophotometry. The relatively new field of deethoxycarbonylations was extended to the area of polymer-supported synthesis resulting in a new tool for preparation of polymer-supported esters.

Desolvated phosphate ions as acyl acceptors in dipolar aprotic media. A non-enzymatic model for formation of “energy-rich” acyl phosphates

n-Decyl phosphate, as the mono benzyltrimethylammonium salt 1, is readily acetylated by 2,4-dinitrophenyl acetate, 2, in dry acetonitrile (MeCN). Reaction is very strongly inhibited by H2O, and acyl phosphate, 3, is not detected with >20 vol% H2O. In these aqueous media ester 2 is hydrolyzed, probably with general-base catalysis by 1, and the acyl phosphate is also slowly hydrolyzed. Potassium dihydrogenphosphate is slowly acetylated by 2, in moist MeCN in the presence of [18]-crown-6 in heterogeneous conditions, but the yield of acetyl phosphate decreases sharply with >10 vol% H2O. Sodium n-decyl phosphate is also acetylated by 2 in dry MeCN in the presence of [15]-crown-5. These acetylations in anhydrous media model enzymic-mediated formation of acyl and other labile phosphates.

Stereospecific Synthesis of Functionalized Ether Phospholipids

A new stereospecific synthesis of functionalized alkyl ether phospholipids is reported. The synthesis is based upon the following: (1) the use of (R)-glycidyl tosylate as a chiral glycerol precursor; (2) the opening of a boron trifluoride catalyzed epoxide ring to introduce the functionalized sn-1-alkyl substituents; (3) the role of tetrahydropyranyl in protecting the sn-2-glycerol position; and (4) the elaboration of the sn-3-carbinol function, via the base hydrolysis of the acetoxy intermediate, obtained from the displacement of the toluenesulfonyl group of the substrate in dipolar aprotic media. Phosphorylation, using two different methods, has led to the development of two major classes of alkyllysophospholipids. For preparation of “modulator-phospholipid” analogues, the substituted glycerol is coupled with 2,2,2-trichloro-tert-butyl phosphodichloridite and an N-protected amino acid ester, while elaboration of the phosphocholine headgroup of the target platelet-activating factor (PAF) analogues is achieved via the 2-chloro-2-oxo-1,3,2-dioxaphospholane/trimethylamine sequence. The synthesis provides rapid and efficient access to both types of phospholipids: (1) construction of the functionalized/substituted glycerol skeleton is achieved in a straightforward four-step sequence in better than 50% overall yield, and (2) phosphitylation or phosphorylation of the respective glycerol intermediates relies on reagents that require minimal use of protecting groups. The phospholipid compounds prepared include (1) the first synthetic analogue exhibiting modulator activity in conjunction with the glucocorticoid-receptor complex and (2) an sn-1-(ω-amino)alkyl derivative of PAF, suitable for introduction of chain-terminal spectroscopic labels for biological and physicochemical studies to elucidate the mechanism of action of this highly potent alkyl ether phospholipid. The synthetic methods described herein have a great deal of flexibility, thus providing convenient general routes to a wide range of alkyl ether phospholipids.

Thermodynamics of cation (alkali-metal) complexation by 5,11,17,23-tetra-tert-butyl[25,26,27,28-tetrakis(2-pyridylmethyl)oxy]- calix(4)arene and the crystal structure–superstructure of its 1:1 complex with sodium and acetonitrile

The interaction of 5,11,17,23-tetra-tert-butyl [25,26,27,28-tetrakis(2-pyridylmethyl)oxy]calix(4)arene 1a with alkali-metal cations in dipolar aprotic media (acetonitrile and benzonitrile) has been investigated. 1H NMR experiments were carried out by adding to the ligand an excess amount of the appropriate metal cation (Li+, Na+, K+) in CD3CN at 298 K. Measurements were taken at different time intervals ranging from 30 min to 10 days. It was found that the kinetics of the process in this solvent is fast. Conductance measurements demonstrated that 1:1 metal cation:ligand stoichiometries are found with these cations in these solvents. Thermodynamic parameters of complexation for this ligand and alkali-metal cations in acetonitrile and in benzonitrile at 298.15 K were derived from titration microcalorimetry. Stability constants were also determined by the competitive potentiometric method using silver electrodes. Excellent agreement is found between the data derived from calorimetry and those derived by potentiometry. The highest stability is found for lithium with this ligand. The results are compared with data previously reported for systems involving a calix(4)arene ester derivative and these cations in the same solvents. The implications of stability constant data on the selective behaviour of this ligand for metal cations in these solvents are discussed. It is shown that this ligand in these solvents is able to discriminate between the smaller cations (Li+ and Na+) and the larger ones (K+ and Rb+). The sodium perchlorate complex of 1a was synthesised and the molecular structure of this complex has been determined from X-ray diffraction data. The substance crystallises in the tetragonal group P4cc with a=21.791(2), c=26.958(3) A and z=8. There are three different complexes in the lattice, two sited on fourfold axes and a third one on a twofold axis. All ligands exhibit a ‘cone’ conformation and the Na+ ion is encapsulated in their hydrophilic pockets with an acetonitrile molecule filling their hydrophobic cavities. Based on 1H NMR, conductimetric, microcalorimetric and X-ray diffraction studies final conclusions are given.

ChemInform Abstract: Acyl Transfer Reactions in Dipolar Aprotic Medium: Desolvated Phosphate Ion as Acyl Acceptor in the Formation of Energy‐Rich Phosphate Compounds

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Acyl transfer reactions in dipolar aprotic medium: desolvated phosphate ion as acyl acceptor in the formation of energy-rich phosphate compounds

The reaction between an acetate ester and n-decylphosphate ions in dipolar aprotic medium provides a system which allows the facile formation of acetyl phosphate derivatives, by means of restricting the quantities of water available in the reacting system; the role of water is explained in terms of the inhibition of the nucleophilic attack of the phosphate group, which is disfavoured by its presence.

ChemInform Abstract: An Improved Asymmetric Synthesis of Piperazic Acids: Retro‐Reaction in the Chiral Oxazolidinone Controlled Di‐Azo Addition Reaction in a Dipolar Aprotic Medium.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

An Improved Asymmetric Synthesis of Piperazic Acids: Retro-Reaction in the Chiral Oxazolidinone Controlled Di-Azo Addition Reaction in a Dipolar Aprotic Medium

The asymmetric addition intramolecular cyclization reaction to produce the piperazic acid precursor 3 was studied. A retroaddition of S -4-(phenylmethyl)oxazolidinyl-5-bromovalerimide to diazo-di-tert-butyl dicarboxylate in DMPU/THF was discovered. A process improvement based on the addition of catalytic tetra-butylammonium iodide to give 3 in 91% yield is reported.