Gluconic acid aqueous solution: A bio-based catalytic medium for organic synthesis

Gluconic acid is non-toxic, non-volatile, non-corrosive, and easily biodegradable chemical, which can be produced from biomass using several methods: oxidation by molecular oxygen using heterogeneous catalysis, enzymatic oxidation, and microbial fermentation. Being highly soluble in water, gluconic acid can form concentrated aqueous solutions, and its 50% aqueous solution has found application as a catalytic medium for organic synthesis. For some reactions, gluconic acid aqueous solutions (GAAS) outperform conventional and green solvents when used as media for organic synthesis. GAAS was found to be particularly efficient in the Knoevenagel condensation, the Michael addition, and multicomponent reactions based on them. These and other chemical transformations utilizing GAAS as a medium are discussed in this review. We also compare the effectiveness of GAAS as a new green catalytic medium and the performance of other solvents and catalysts.     

Development of catalytic reactions using water as a solvent]

In recent years, organic reactions in aqueous media have attracted much attention, not only because these reactions eliminate the necessity of vigorous drying of solvents and substrates, but also because unique reactivity and selectivity are often observed in the aqueous reactions. Furthermore, organic reactions in water may lead to the development of environmentally friendly chemical processes. We have now developed various types of catalytic organic reactions in aqueous media. Catalytic asymmetric aldol reactions in aqueous media have attained by using rare earth metal triflates and a chiral multi-dentate ligand. Lewis acid catalysis has become feasible in water by using combinations of water-compatible Lewis acidic cations and anionic surfactants. These new catalysts were found to form stable colloidal dispersions and catalyze various reactions in water. Moreover, Br?nsted acid- and palladium-catalyzed reactions in water have also been performed with the aid of surfactants.     

羧烷基化合成萘普生工艺改进

１－溴－２－甲氧基萘与０－对在苯磺酰乳酸乙酯（１）在无水氯化铝催化下化Ｆｒｉｅｄｅｌ－Ｃｒａｆｔｓ反应，还原脱溴直接合成ｄｌ－１ａ萘普生（３），以上反应均在“一锅”内完成，收率达９５。     

Development of radical reactions in water aimed at environmentally benign synthetic reactions

The aqueous medium radical reactions of a variety of imine derivatives such as oxime ether, oxime, hydrazone, nitrone, and N-sulfonylimine were investigated. Triethylborane-mediated intermolecular alkyl radical addition to glyoxylic oxime ether, oxime, and nitrone in water proceeded smoothly to give alpha-amino acid derivatives in good yields. Alkyl radical addition to N-sulfonylimine proceeded in aqueous media using zinc as a radical initiator. The zinc-mediated radical reaction of the hydrazone with a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities, which could be converted into enantiomerically pure alpha-amino acids. The indium-mediated radical reactions provide new opportunities for carbon-carbon bond formation such as alkylation reactions of imines and 1,4-addition to electron-deficient olefins. The indium-mediated tandem reactions also proceeded effectively via two carbon-carbon bond-forming processes for the preparation of various types of functionalized cyclic compounds.     

Ethyl lactate as a potential green solvent to extract hydrophilic (polar) and lipophilic (non-polar) phytonutrients simultaneously from fruit and vegetable by-products

Phytonutrients extracted from natural resources are receiving much attention among researchers due to their highly antioxidative characteristics which prevent several degenerative diseases including cardiovascular diseases and cancers. These nutraceutical compounds can be used in food, pharmaceutical and cosmetic products as natural antioxidants, preservatives, colourants and functional foods. Huge volume of food wastes are generated from the processing industry and these low-value food residues are rich in various phytonutrients worth recovering. This approach of valorisation reduces the generation of food wastes and is cost-effective considering the cheap feedstock, reduced waste management expenses and high market value of extracted compounds. In light of the health and safety risks posed by commonly used organic extraction solvents derived from the petrochemical industry, there is a need to recover the phytonutrients using green, sustainable and efficient solvents that are safe for human consumption. This work discusses ethyl lactate as a safe, green, efficient and potentially cheap solvent to recover phytonutrients from fruit and vegetable by-products. Ethyl lactate is compared with other organic solvents commonly used from the aspects of safety, environmental impacts and efficiency. Current challenges when employing ethyl lactate are also discussed.     

Cyrene: A bio-based sustainable solvent for organic synthesis

Cyrene (dihydrolevoglucosenone) is a green dipolar aprotic solvent prepared by pyrolysis of cellulose-containing biomass. Cyrene possesses a beneficial occupational health and safety profile combined with good biodegradability without NO_x or SO_x production. Since 2014, when Cyrene was for the first time introduced as a green solvent, it has attracted much attention in different fields. In this review, we discuss organic reactions, for which Cyrene was employed to play the role of medium. Significant progress was achieved in the replacement of conventional aprotic solvents by Cyrene as a safe and sustainable alternative. Cyrene demonstrated to be an effective medium for diverse chemical transformations, from carbon-carbon coupling reactions to bio-catalyzed processes and polymerization. The applications of Cyrene as a co-solvent (e.g. in form of aqueous solutions) for organic synthesis are also discussed.     

Preparation and properties of S-nitroso-L-cysteine ethyl ester, an intracellular nitrosating agent

In this report, a protocol for the preparation of the hydrochloride of S-nitroso-L-cysteine ethyl ester (SNCEE.HCl; 2) is presented. The synthesis of 2 has been targeted because S-nitroso-L-cysteine (SNC; 2b), which is extensively used for trans-S-nitrosation of thiol-containing proteins, has a limited ability of crossing cellular membranes. The nitrosothiol 2 was prepared via direct S-nitrosation of the hydrochloride of L-cysteine ethyl ester (CEE.HCl; 1a) with ethyl nitrite. 2 is relatively stable in crystal form and when neutralized to SNCEE (2a) in aqueous solutions treated with chelators of metal ions. Traces of metal ions, however, triggered the decomposition of 2a to nitric oxide and a S-centered radical, which were detected by ESR spectrometry. In contrast to 2b, 2a is a lipophilic compound that was taken up by human neutrophils. The latter process was paralleled by inhibition of the NADPH oxidase-dependent generation of superoxide anion radicals, presumably via reaction(s) of intracellular trans-S-nitrosation. Intracellular accumulation of S-nitrosothiols was observed with 2a but not with 2b. It is expected that the use of 2a will be advantageous when intracellular reactions of trans-S-nitrosation are to be studied.     

Dissolution rates of corticoid solutions dispersed on silicas

Two nonporous and three porous amorphous silicas were used as dispersion media to convert corticoid solutions into free-flowing powders. The corticoids (prednisone, prednisolone, and hydrocortisone) were dissolved in N,N-dimethylacetamide-polyethylene glycol 400 (7:3 v/v) and their 10% (w/v) solutions were mixed with the silicas (1:3 v/w). Dissolution rates of the corticoids from such powdered solutions were more rapid than their micronized powders in various aqueous media.     

The swelling properties of poly(2-hydroxyethyl methacrylate) hydrogels polymerized by gamma-irradiation and chemical initiation

The swelling behaviour of polyHEMA hydrogels in aqueous solutions of various compounds has been investigated. Gels polymerized using a chemical initiator attained a higher equilibrium hydration in aqueous solutions than those polymerized by ionizing radiation. The difference in equilibrium hydration has been explained in terms of the effect of residual initiator on swelling. Aqueous solutions of sodium chloride, sucrose and glucose were found to dehydrate the gels, while solutions of phenol, urea, acetic acid, acetamide, ethanol, sodium acetate and ethyl urea caused swelling. The extent of swelling was a function of the osmotic activity, size, lipophilicity and number of hydrogen bonding groups of the solute molecule. A linear relationship was found between the swelling rate and the concentration of cross-linking agent in the gel.     

Studies on estrification and sulphonation of riboflavin in the environment of highly concentrated sulphuric acid

The article presents investigations of riboflavin reactions in aqueous solutions of sulphuric acid. Analysis of UV/VIS, 1H NMR spectra and TLC indicates that at the beginning of the reaction ester of riboflavin were obtained and then sulphonation reaction took place. From the analysis of UV/VIS spectra the kinetics of the reaction was calculated, using own computer program.     

Effect of food dyes on radicals in aqueous media

The rates of reaction of photogenerated hydroperoxy and hydroxyl radicals on the photostability of aqueous solutions of dequalinium chloride irradiated with simulated sunlight at 38 ± 1°C have been investigated, with and without the addition of amaranth and quinoline yellow. These reactions follow second-order kinetics and the dyes tested markedly increase the rate constants of the reactions. Hydroperoxy radicals react with hydroxyl radicals preferentially to the dequalinium chloride resulting in lower reaction rate constants for the latter. Acetaldehyde was used as a scavenger of hydroperoxy radicals.     

Stability of batanopride hydrochloride in aqueous solutions.

The degradation of batanopride hydrochloride, an investigational antiemetic drug, was studied in aqueous buffer solutions (pH 2-10; ionic strength, 0.5; 56 degrees C) in an attempt to improve drug stability for parenteral administration. Degradation occurs by two different mechanisms depending on the pH of the solution. In acidic media (pH 2-6), the predominant reaction was intramolecular cyclization followed by dehydration to form a 2,3-dimethylbenzofuran. There was no kinetic or analytical (high-performance liquid chromatography) evidence for the formation of an intermediate; therefore, the rate of dehydration must have been very rapid compared with the rate of cyclization. In alkaline media (pH 8-10), the primary route of degradation was cleavage of the C-O alkyl ether bond. In the intermediate pH range (pH 6-8), both reactions contributed to the overall degradation. Both degradation reactions followed apparent first-order kinetics. The pH-rate profile suggests that batanopride hydrochloride attains its optimal stability at pH 4.5-5.5. Citrate buffer was catalytic at pH 3 and 5, and phosphate buffer was catalytic at pH 8. No catalytic effect was observed for the borate buffer at pH 9-10.     

Cryo-irradiation as a terminal method for the sterilization of drug aqueous solutions

The aim of this study is to evaluate the specificities of the irradiation of drugs in frozen aqueous solution. The structures of the degradation products were determined to gain insight into the radiolysis mechanisms occurring in frozen aqueous solutions. Metoclopramide hydrochloride and metoprolol tartrate were chosen as models. The frozen solutions were irradiated at dry ice temperature by high energy electrons at various doses. The drug purity (chemical potency) and the radiolysis products were quantified by HPLC-DAD. Characterization of the degradation products was performed by LC–APCI–MS–MS. The structures of the radiolysis products detected in irradiated frozen aqueous solutions were compared to those detected in solid-state and aqueous solutions (previous studies). For both metoclopramide and metoprolol, solute loss upon irradiation of frozen aqueous solutions was negligible. Five radiolysis products present in traces were identified in irradiated metoclopramide frozen solutions. Three of them were previously identified in solid-state irradiated metoclopramide crystals. The two others were formed following reactions with the hydroxyl radical (indirect effect). Only one fragmentation product was observed in irradiated metoprolol frozen solutions. For both drugs, radiosterilization of frozen solutions, even at high doses (25 kGy), was found to be possible.     

Pepsin-catalyzed peptide synthesis in organic media: studies with free and immobilized enzyme

Pepsin-catalyzed synthesis of protected peptides was studied in two-phase systems containing up to 50% (by volume) of aqueous phase. A methodological study was carried out to determine the optimum conditions for the synthesis of the model protected peptide Z-Phe-Phe-OMe. Several parameters such as concentrations of carboxylic and amino components, pH of the aqueous phase, ratio of organic to aqueous phase volumes and nature of the organic solvent were investigated. It was observed that the most hydrophobic solvents produced the best yields, despite the low solubility of substrates in these media. The log P of the solvent could be used to predict the solvent effect over the reaction yields. Pepsin immobilized by adsorption onto the solid supports Celite and Chromosorb was employed to perform a study of secondary specificity of the enzyme in organic media through the coupling between Z-X-Phe-OH (X = Ala, Asp, Glu, Gly, Phe, Ile, Val, Trp and Tyr) and Phe-OMe. This investigation was performed in two solvent systems: (A) ethyl acetate:citrate buffer pH 4.5 (98:02, v:v) and (B) acetonitrile:citrate buffer pH 4.5 (96:04, v:v). Reaction rate data showed that pepsin had a preference for more hydrophilic substituents in the P₂ position. These data are in contrast to the literature for a similar reaction performed in predominantly aqueous media. Thus, for mainly organic media, partition phenomena are very important and may cause an apparent modification of enzyme specificity.     

Enol esters as potential pro-drugs II. In vitro aqueous stability and enzyme-mediated hydrolysis of several enol esters of acetophenone

Several α-acyloxystyrenes were synthesized and evaluated as models of enol esters which might be used in pro-drug design. Their stabilities were evaluated in aqueous buffered solutions at various pH values and temperatures, and in human and rat plasma and tissue homogenates at 37°C. The enol esters studied were relatively stable in neutral aqueous media, but most hydrolyzed rapidly and completely to yield the parent ketone (acetophenone) with the aid of enzymatic catalysis in the biological media used. The aqueous and enzymatic rates of hydrolysis were substantially affected by the nature of the acyl group. The results of this study indicate that enol esters are rather stable yet bioreversible derivatives of ketones and therefore may be useful as pro-drugs of agents containing enolizable carboxyl groups.     

Thiol addition to quinones: model reactions for the inactivation of thymidylate synthase by 5-p-benzoquinonyl-2'-deoxyuridine 5'-phosphate

The reaction of methyl mercaptoacetate (5) with phenyl-p-benzoquinone (6) or 5-p-benzoquinonyl-3',5'-di-O-acetyl-2'-deoxyuridine (10) resulted in the formation of the three possible adducts to the quinone rings of 6 and 10; an additional product in the reaction with 10 was the unsubstituted hydroquinone (14). Both reactions were found to be solvent dependent; in buffered aqueous acetonitrile the meta and para adducts of 10 were formed in the ratio of 2:1. In ethyl acetate the ortho adduct and the reduction product of 10 were isolated in a ratio of 2:3. The second-order rate constant for the reaction of 5 with 10 in acetonitrile was 0.53 M-1 s-1; the reaction was accelerated by the addition of water. Although the initially proposed mechanism-based enzyme inactivation cannot be excluded, the results of the model reactions support the alternative mechanism, active-site thiol addition to the quinone ring. If this is true the title compound would be classed as an affinity label, not a mechanism-based inhibitor.     

Noncovalent dimerization of paclitaxel in solution: evidence from electrospray ionization mass spectrometry

Paclitaxel, a unique antimitotic chemotherapy agent that inhibits cell division by binding to microtubules and prevents them from "depolymerizing," has received widespread interest because of its efficacy in fighting certain types of cancer, including breast and ovarian cancer. Paclitaxel undergoes aggregation at millimolar concentrations in both aqueous media and solvents of low polarity (mimicking hydrophobic environments). Its aggregation may have impact on its aqueous stability and its ability to stabilize microtubules. Here, we investigated the dimerization phenomenon of paclitaxel by electrospray ionization mass spectrometry (ESI-MS). Paclitaxel dimers were stable in solutions of acetonitrile/aqueous ammonium acetate (80/20) and aqueous sodium acetate/acetonitrile (92/8 or 95/5) at various pH values. Additional experiments using solution-phase hydrogen/deuterium exchange were employed to ascertain whether or not the observed dimers were formed in solution or as an artifact of the ESI process by ion-molecule reaction. The evidence supports formation of the dimer in solution, and the approach used can be extended to investigation of other types of drug-drug interactions.     

Does peroxynitrite partition between aqueous and gas phases? Implication for lipid peroxidation

Relative reactivity of alkane and alkylbenzene oxidation by peroxynitrite has been determined in acidic aqueous solutions. The observed data are explained assuming that the reaction simultaneously proceeds in both the gas and the liquid phases. The selectivity in the gas phase was found to be very similar to that of discrete hydroxyl radicals. The ability of peroxynitrite to react with organic substrates in the gas phase suggests that similar processes may occur in lipophilic media. The reaction mechanism and implication for lipid peroxidation are discussed.     

Methodology for studying antioxidant activity and mechanisms of action of antioxidants

A brief survey of the main reactions involved in lipid peroxidation and of the principal methods used for the detection of lipid peroxidation in authentic food, in model systems and in biological material is given. The reaction of phenolic antioxidants with various radicals generated during lipid peroxidation and the synergism between individual antioxidants are outlined. The biological consequences of lipid peroxidation and the protective properties of antioxidants are discussed. In addition, the scavenger action of antioxidants toward inorganic oxygen radicals is described, and it is demonstrated that propyl gallate surpasses butylated hydroxyanisole and butylated hydroxytoluene in its capacity to remove hydroxyl radicals and superoxide radicals from aqueous model media and from biological material. Biochemical actions of antioxidants that may be involved in the anti-carcinogenic and proliferation-stimulating effects of antioxidants in vivo are listed.     

The influence of carbohydrates and polyhydric alcohols on the stability of cephalosporins in aqueous solution

The kinetics of the degradation of cephaloridine, cephalothin and cefazolin in aqueous solutions containing various carbohydrates (glucose, fructose, sucrose and dextrans) or polyhydric alcohols (sorbitol, mannitol and glycerol) was studied over the pH range 5–12 at 35°C. The degradation rate increased linearly with the hydroxy compound concentration up to 15% at constant pH for pH > 6.5. The rate-accelerating effect of the compounds was directly proportional to the hydroxide ion activity up to pH about 11 above which value the rate of reactions levelled off with increasing pH as demonstrated for glucose. Maximal stability of the cephalosporins in solutions containing carbohydrates or polyhydric alcohols is attained at pH 5–6.5. It is proposed that the rate-accelerating effect of the hydroxy compounds is due to a nucleophilic reaction mechanism involving opening of the cephalosporin β-lactam moiety by an alkoxide ion derived from proton ionization of one of the hydroxyl groups in the compounds.