Alcohol Side Research Articles

Dehydrogenative Conversions of Aldehydes and Amines to Amides Catalyzed by a Nickel(II) Pincer Complex

A C-N cross-coupling approach involving oxidative amidations of aromatic aldehydes in the presence of an amide-based nickel(II) pincer catalyst (2) is demonstrated. Upon optimization, quick reaction times (15 min) and an ideal temperature (25 °C) were established and implemented for the conversion of 33 different amide products using only 0.2 mol% of catalyst. Moderate to good turnover numbers (TONs) were obtained for secondary benzamide products, and moderate TONs were obtained for tertiary benzamide products, with the highest turnover number calculated for the 4-chloro-N-(3-phenylpropyl)benzamide product (4i, 309). Gas chromatographic–mass spectrometric (GC–MS) analysis also indicates the formation of alcohols in different reactions, indicating an oxidative amidation process. Kinetic studies were performed by varying the amount of catalyst, aldehyde, LiHMDS base, and amine substrate to determine the order of reaction for each component. Benzaldehyde and benzaldehyde-d6 were reacted with benzylamine, and the kH/kD ratio was determined to understand the rate-determining step. Isotope labeling further revealed that deuterium was being transferred to both the alcohol side product and the target amide product. With the help of kinetic data and UV–visible spectra, a mechanism for the amidation process via the catalyst (2) is proposed through a Ni(I)–Ni(III) pathway.

Functionalized Alkylidenecyclobutanes from a Cyclopent‐2‐enone Substrate via a Tandem Photochemical Transformation and an Allylic Substitution Protocol

AbstractA four‐step metal‐free procedure is described for the transformation of 4‐hydroxy‐2‐methylcyclopent‐2‐enone derivatives into highly functionalized E‐alkylidenecyclobutanes featuring oxygenated tetrasubstituted centers. The key intermediate is a (cyclobutenyl)propane‐1,3‐diol diester, easily accessed via a tandem photochemical reaction, which undergoes an original Brønsted acid‐catalyzed allylic substitution reaction with alcohols to give the title products with ester‐protected primary alcohol side chains.

Analysis of Volatile Esters and Alkanoic Acids by an Atmospheric Pressure Corona Discharge Ionization Collision-Induced Dissociation Mass Spectrometry in Positive-Ion Mode: Ionization, Fragmentation Patterns, and Discrimination between Isomeric Compounds.

The ionization and fragmentation patterns of 24 compounds with elemental composition of CmH2mO2, including isomeric esters and alkanoic acids, were investigated by atmospheric pressure corona discharge ionization collision-induced dissociation (CID) mass spectrometry in the positive-ion mode. All compounds were ionized as protonated molecules and NH4+ adducts. In addition, fragment ions were observed in mass spectra of esters other than methyl esters, which are owing to the dissociation of the alkyl group in the alcohol side from the protonated molecules. In CID spectra, protonated alkanoic acids/methyl esters split off H2O/CH3OH and CO or the alkyl group in the acid side, depending on the carbon chain length. Protonated esters (other than methyl esters) mainly fragmented the alkyl group in the alcohol side. These general rules on ionization and fragmentation patterns can provide relevant information on the discrimination of isomers.

Detoxification activity of bioactive food compounds against ethanol-induced injuries and hangover symptoms: A review.

Alcohol drinking is a popular activity among adolescents in many countries, largely due to its pleasant, relaxing effects. As a major concern, ethanol consumption put the drinkers at risk of nutrients' deficiency due to the disordered eating, anorexia, and malabsorption of nutrients. Moreover, alcohol drinking may lead to the development of hangover symptoms including diarrhea, thirsty, fatigue, and oxidative stress. A broad range of functional food components with antioxidant and/or anti-inflammatory properties including pectin, aloe vera polysaccharides, chito-oligosaccharides, and other herbal components have been explored due to their detoxification effects against ethanol. The underlying anti-hangover mechanisms include reducing the intestinal absorption of ethanol or its metabolites, increasing the activity of ethanol metabolizing enzymes, development of fatty acid β-oxidation in mitochondria, inhibition of inflammatory response, blocking the target receptors of ethanol in the body, and possession of antioxidant activity under the oxidative stress developed by ethanol consumption. Therefore, the development of bioactive food-based therapeutic formula can assist clinicians and also drinkers in the alleviation of alcohol side effects.

Organocatalyzed enantio- and diastereoselective isomerization of prochiral 1,3-cyclohexanediones into nonalactones bearing distant stereocenters.

The lactonization of 2-(2-nitrophenyl)-1,3-cyclohexanediones containing an alcohol side chain and up to three distant prochiral elements is reported by isomerization under the mediation of simple organocatalysts such as quinidine. Through a process of ring expansion, strained nonalactones and decalactone are produced with up to three stereocenters in high er and dr (up to 99 : 1). Distant groups, including alkyl, aryl, carboxylate and carboxamide moieties, were examined.

Tricky Isomers-The Evolution of Analytical Strategies to Characterize Plasmalogens and Plasmanyl Ether Lipids.

Typically, glycerophospholipids are represented with two esterified fatty acids. However, by up to 20%, a significant proportion of this lipid class carries an ether-linked fatty alcohol side chain at the sn-1 position, generally referred to as ether lipids, which shape their specific physicochemical properties. Among those, plasmalogens represent a distinct subgroup characterized by an sn-1 vinyl-ether double bond. The total loss of ether lipids in severe peroxisomal defects such as rhizomelic chondrodysplasia punctata indicates their crucial contribution to diverse cellular functions. An aberrant ether lipid metabolism has also been reported in multifactorial conditions including Alzheimer’s disease. Understanding the underlying pathological implications is hampered by the still unclear exact functional spectrum of ether lipids, especially in regard to the differentiation between the individual contributions of plasmalogens (plasmenyl lipids) and their non-vinyl-ether lipid (plasmanyl) counterparts. A primary reason for this is that exact identification and quantification of plasmalogens and other ether lipids poses a challenging and usually labor-intensive task. Diverse analytical methods for the detection of plasmalogens have been developed. Liquid chromatography–tandem mass spectrometry is increasingly used to resolve complex lipid mixtures, and with optimized parameters and specialized fragmentation strategies, discrimination between ethers and plasmalogens is feasible. In this review, we recapitulate historic and current methodologies for the recognition and quantification of these important lipids and will discuss developments in this field that can contribute to the characterization of plasmalogens in high structural detail.

Phosgene-free synthesis of N-methyl-N′,N′-diphenylurea

Akardite II (AK-II, N-methyl-N′,N′-diphenylurea) is a well-known stabilizer for nitrocellulose (NC) propellants as it scavenges NOx. Currently, AK-II is produced using phosgene, a highly toxic gas. An alternative, two-step synthesis route is presented here that does not rely on phosgene. First, symmetrical organic carbonates (R2CO3, with R ​= ​Me, Et, or Ph) and diphenylamine react to form their corresponding carbamates in good yields for R ​= ​Me and Et (80% and 57%) and low yield for R ​= ​Ph (9%), catalyzed by 3-methyl-1-butylimidazolium chloride ([BMIM]Cl). The carbamate species are suggested to be formed in an equilibrium reaction. Evaporation of the alcohol side products pushes the equilibrium to the carbamate product. The second step converts the diphenyl carbamates into the targeted compound by treatment with (mono)methylamine (MMA), with reversed yield trend (4% for R ​= ​Me and Et, 81% for R ​= ​Ph). For the alkyl carbamates, the formation of AK-II appears to run in parallel with an MMA-alkylation reaction, which severely lowers the product yield. Overall, the synthesis of AK-II via the carbamate route is feasible, yet the carbonate side groups should be chosen carefully to obtain a high overall yield.

Alcohol flexible HD single cylinder diesel engine tests with separate dual high pressure direct fuel injection

Both greenhouse gas (GHG) emissions and local emissions from heavy duty (HD) Diesel engines must be greatly reduced to make transportation sustainable and comply with increasingly stringent emissions regulations. The fuel flexible engine concept for HD Diesel engines uses a dual fuel direct injection system in which ignition of the main alcohol fuel, either methanol or ethanol, is induced by a small Diesel pilot injection delivered via a separate direct injector. The objective of this investigation was to find ways to combine the advantages of conventional Diesel engines with the advantages of low carbon fuels and to thereby bypass the soot-NOx-trade-off. Experiments were conducted using a modified single-cylinder HD engine and three fuels (methanol, ethanol, and a reference Diesel fuel) to determine how the choice of fuel affected the engine’s combustion behaviour, emissions and fuel efficiency. Injection pressures on the alcohol side were varied up to 1500 bar and the investigation was carried out at low, medium and high speed-load points. The alcohol fuels significantly outperformed Diesel fuel under all tested conditions (with and without exhaust gas recirculation (EGR)). Indicated thermal efficiency was increased by up to 3.5%-points and simultaneously soot emissions were lowered by a factor of 40 or more and NOx by 20%. Combustion stability and emissions were in the same range as for Diesel but replacing more than 95 % of the fossil Diesel with an alcohol fuel.

Thermodynamic destabilization of azurin by four different tetramethylguanidinium amino acid ionic liquids

The thermal unfolding of the copper redox protein azurin was studied in the presence of four different amino acid-based ionic liquids (ILs), all of which have tetramethylguanidium as cation. The anionic amino acid includes two with alcohol side chains, serine and threonine, and two with carboxylic acids, aspartate and glutamate. Control experiments showed that amino acids alone do not significantly change protein stability and pH changes anticipated by the amino acid nature have only minor effects on the protein. With the ILs, the protein is destabilized and the melting temperature is decreased. The two ILs with alcohol side chains strongly destabilize the protein while the two ILs with acid side chains have weaker effects. Unfolding enthalpy (ΔHunf°) and entropy (ΔSunf°) values, derived from fits of the unfolding data, show that some ILs increase ΔHunf°while others do not significantly change this value. All ILs, however, increase ΔSunf°. MD simulations of both the folded and unfolded protein conformations in the presence of the ILs provide insight into the different IL-protein interactions and how they affect the ΔHunf° values. The simulations also confirm that the ILs increase the unfolded state entropies which can explain the increased ΔSunf° values.

A Novel Reverse Phase HPLC Method for the Quantification of Potential Genotoxic Impurities in Doripenem Monohydrate: A Broad-Spectrum Carbapenem Antibiotic Drug

A novel sensitive gradient reverse phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for the quantification of potential genotoxic impurities in doripenem monohydrate (DORIBAX) drug substance, namely mono-p-nitrobenzyl malonate, 1β-methyl bicyclic ketoester, desilylated β-keto ester, 1β-methyldiazoazetidinone, deprotected doripenem side chain, N-protected mercapto alcohol, protected doripenem and doripenem side chain. The analysis performed on Alliance Waters e2695 separation module on C18 (250 × 4.6) mm, 5 μm (make: Inertsil) column, oven temperature maintained at 40 ºC and UV detection at 270 nm. The separation was accomplished using buffer (pH 6.0 ± 0.05) and acetonitrile in the ratio of 98:2 v/v as mobile phase-A and acetonitrile as mobile phase-B, flow rate: 1.0 mL/min and injection volume: 50 μL. The proposed method was validated as per ICH guidelines in terms of limit of detection (LOD), limit of quantification (LOQ), linearity, precision, accuracy and specificity.

Revealing Structural Modifications of Lignin in Acidic γ-Valerolactone-H2O Pretreatment.

γ-valerolactone (GVL)/H2O/acid solvent mixtures has been used in chemical pretreatment of lignocellulosic biomass, it was claimed that GVL lignins were structurally close to proto (native) lignins, or having low molecular weight with narrow polydispersity, however, the structural changes of GVL lignins have not been investigated. In this study, β-O-4 (β-aryl ether, GG), β-5 (phenylcoumaran), and β-β (resinol) lignin model compounds were treated by an acidic GVL-H2O solvent system, a promising pretreatment of lignocellulose for biomass utilization, to investigate the structural changes possibly related to the lignin involved. NMR characterization of the products isolated from the treated GG indicated that a phenyl dihydrobenzofuran, having typical C-H correlations at δC/δH 50.74/4.50 and 93.49/4.60 ppm in its HSQC spectrum, was produced from GG. In the pretreatment, the released formaldehyde from GG reacted fast with GG to form a novel 1,3-dioxane intermediate whose characteristic HSQC signals were: δC/δH 94.15–94.48/4.81–5.18 ppm and 80.82–83.34/4.50–4.94 ppm. The β-5 model, dihydrodehydrodiconiferyl alcohol, was converted into phenylcoumarone and stilbene having benzaldehyde that resulted from the allyl alcohol side chain. The β-β model, syringaresinol, was isomerized to form a mixture of syringaresinol, epi-, and dia-syringaresinol although being degraded slightly.

Highly diastereoselective synthesis of 3-methylenetetrahydropyrans by palladium-catalyzed oxa-[4 + 2] cycloaddition of 2-alkenylbenzothiazoles.

A highly diastereoselective synthesis of 3-methylenetetrahydropyrans via palladium-catalyzed oxa-[4 + 2] cycloaddition of 2-alkenylbenzothiazoles with allyl carbonates bearing a nucleophilic alcohol side chain is presented. This synthetic methodology tolerates a wide variety of 2-alkenylbenzothiazoles and afforded the desired 3-methylenetetrahydropyrans in good yields and excellent dr. In addition, further derivatizations resulted in new scaffolds, making them useful synthetic precursors.

Strong Microheterogeneity in Novel Deep Eutectic Solvents.

With the increasing application of template assisted syntheses in deep eutectic solvents and successful application of hydrophobic deep eutectic solvents in extraction processes, where microheterogeneity plays a major role, suggestions for novel deep eutectic solvents which exhibit strong microheterogeneity are desirable. Therefore, classical molecular dynamics simulations were carried out on deep eutectic solvent systems constructed of choline chloride and some of its derivatives mixed with ethylene glycol in a molar composition of 1 : 2 since this is the optimal parent composition. The derivatives consisted of a series of elongated alkyl side chains and elongated alcohol side chains. Of these series only choline chloride ethylene glycol has been investigated experimentally, the other systems are suggested and theoretically investigated as possible target for synthesis. Our domain analysis supported by the clear distinction of polar and nonpolar parts from the electrostatic potentials reveals that strong microheterogeneity within these novel hypothetical deep eutectic solvents exists. Rather stretched than crumbled side chains maximize possible interaction sites for both polar and nonpolar parts which make the suggested compounds valuable objectives for experiments in order to exploit the microheterogeneity in deep eutectic solvents.

1,4-Benzodioxane Lignans: An Efficient, Asymmetric Synthesis of Flavonolignans and Study of Neolignan Cytotoxicity and Antiviral Profiles.

1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4-benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3-deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4-benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity.

Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents.

We describe the preparation and evaluation of novel indoline derivatives with potent antioxidant and anti-inflammatory activities for the treatment of pathological conditions associated with chronic inflammation. The indolines are substituted at position 1 with chains carrying amino, ester, amide, or alcohol groups, and some have additional substituents, Cl, MeO, Me, F, HO, or BnO, on the benzo ring. Concentrations of 1 pM to 1 nM of several compounds protected RAW264.7 macrophages against H2O2 induced cytotoxicity and LPS induced elevation of NO, TNF-α, and IL-6. Several derivatives had anti-inflammatory activity at 1/100th of the concentration of unsubstituted indoline. Four compounds with ester, amine, amide, or alcohol side chains injected subcutaneously in mice at a dose of 1 μmol/kg or less, like dexamethasone (5.6 μmol/kg) prevented LPS-induced cytokine elevation in the brain and peripheral tissues. Subcutaneous injection of 100 μmol/kg of these compounds caused no noticeable adverse effects in mice during 3 days of observation.

New tetramic acid derivatives from the deep-sea-derived fungus Cladosporium sp. SCSIO z0025

Eight new tetramic acid derivatives, cladosporiumins A–H (1–8) were isolated from a culture broth of Cladosporium sp. SCSIO z0025 derived from the deep-sea sediment collected from Okinawa Trough. Their structures were elucidated by extensive spectroscopic data analysis. Compounds 1–3 were unique 3-acyltetramic acids with a hexyl enic alcohol side chain and a six-membered lactone ring substituted at C-3 of the 2, 4-pyrrolidinedione skeleton. The absolute configurations of chiral carbons of the 2, 4-pyrrolidinedione unit in 1–4 and 7 were established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. And the absolute configurations of chiral carbons of the six-membered lactone ring in 1–3 were established by density functional theory calculation of their 13C NMR chemical shifts. In addition, all the compounds were tested for cytotoxic, antibacterial, anti-biofilm, and AchE inhibitory activities.

A triad of residues is functionally transferrable between 5-HT3 serotonin receptors and nicotinic acetylcholine receptors

Cys-loop receptors are pentameric ligand-gated ion channels that facilitate communication within the nervous system. Upon neurotransmitter binding, these receptors undergo an allosteric activation mechanism connecting the binding event to the membrane-spanning channel pore, which expands to conduct ions. Some of the earliest steps in this activation mechanism are carried out by residues proximal to the binding site, the relative positioning of which may reflect functional differences among members of the Cys-loop family of receptors. Herein, we investigated key side-chain interactions near the binding site via mutagenesis and two-electrode voltage-clamp electrophysiology in serotonin-gated 5-HT3A receptors (5-HT3ARs) and nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes. We found that a triad of residues aligning to Thr-152, Glu-209, and Lys-211 in the 5-HT3AR can be exchanged between the homomeric 5-HT3AR and the muscle-type nAChR α-subunit with small functional consequences. Via triple mutant cycle analysis, we demonstrated that this triad forms an interdependent network in the muscle-type nAChR. Furthermore, nAChR-type mutations of the 5-HT3AR affect the affinity of nicotine, a competitive antagonist of 5-HT3ARs, in a cooperative manner. Using mutant cycle analyses between the 5-HT3A triad, loop A residues Asn-101 and Glu-102, β9 residue Lys-197, and the channel gate at Thr-257, we observed that residues in this region are energetically linked to the channel gate and are particularly sensitive to mutations that introduce a net positive charge. This study expands our understanding of the differences and similarities in the activation mechanisms of Cys-loop receptors.

Palladium‐catalyzed Oxa‐[4+2] Annulation of para‐Quinone Methides

AbstractA palladium‐catalyzed oxa‐[4+2] annulation of para‐quinone methides with allyl carbonates bearing a nucleophilic alcohol side chain has been developed. This method provided an efficient strategy to the construction of 2‐oxaspiro‐cyclohexadienones via 1,6‐conjugated addition‐mediated allylation in moderate to good yields. Preliminary results on asymmetric derivatives promised potential in the synthesis of enantioenriched frameworks.magnified image

The Enigmatic P450 Decarboxylase OleT Is Capable of, but Evolved To Frustrate, Oxygen Rebound Chemistry.

OleT is a cytochrome P450 enzyme that catalyzes the removal of carbon dioxide from variable chain length fatty acids to form 1-alkenes. In this work, we examine the binding and metabolic profile of OleT with shorter chain length (n ≤ 12) fatty acids that can form liquid transportation fuels. Transient kinetics and product analyses confirm that OleT capably activates hydrogen peroxide with shorter substrates to form the high-valent intermediate Compound I and largely performs C-C bond scission. However, the enzyme also produces fatty alcohol side products using the high-valent iron oxo chemistry commonly associated with insertion of oxygen into hydrocarbons. When presented with a short chain fatty acid that can initiate the formation of Compound I, OleT oxidizes the diagnostic probe molecules norcarane and methylcyclopropane in a manner that is reminiscent of reactions of many CYP hydroxylases with radical clock substrates. These data are consistent with a decarboxylation mechanism in which Compound I abstracts a substrate hydrogen atom in the initial step. Positioning of the incipient substrate radical is a crucial element in controlling the efficiency of activated OH rebound.

Peptide—protein interactions within human hair keratins

We selected 1235 decapeptides from human hair proteins encoded by human genes of keratins and keratin associated proteins. The peptides were linked to glass arrays and screened for their affinity towards a solution of human hair extracted keratin fraction. Based on the physicochemical properties of the peptides, ten variables were studied: content of different types of amino acid side chains (cysteine, hydrophobic, polar, basic, acidic, aromatic rings, amide, alcohol side chains), isoelectric point, and net charge. We found differences statistically significant on the binding affinity of peptides based on their content of cysteine, hydrophobic and polar amino acids, mainly containing alcohols. These results point to the formation of hydrophobic interactions and disulfide bonds between small peptides and human hair keratins as the main driving forces for the interaction of possible cosmetic peptides, namely designed to strength human hair. As so, our results enlighten the nature of the interaction of keratin based materials with human hair, which are claimed to enhance hair fiber strength, and enable a more directed and sustained hair care peptide design.