Polyethylene, whose surface has been modified by UV irradiation, induces cytotoxicity: A comparison with microplastics found in beaches.

Microplastics, plastic particles 5 mm or less in size, are abundant in the environment; hence, the exposure of humans to microplastics is a great concern. Usually, the surface of microplastics found in the environment has undergone degradation by external factors such as ultraviolet rays and water waves. One of the characteristics of changes caused by surface degradation of microplastics is the introduction of oxygen-containing functional groups. Surface degradation alters the physicochemical properties of plastics, suggesting that the biological effects of environmentally degraded plastics may differ from those of pure plastics. However, the biological effects of plastics introduced with oxygen-containing functional groups through degradation are poorly elucidated owing to the lack of a plastic sample that imitates the degradation state of plastics found in the environment. In this study, we investigated the degradation state of microplastics collected from a beach. Next, we degraded a commercially available polyethylene (PE) particles via vacuum ultraviolet (VUV) irradiation and showed that chemical surface state of PE imitates that of microplastics in the environment. We evaluated the cytotoxic effects of degraded PE samples on immune and epithelial cell lines. We found that VUV irradiation was effective in degrading PE within a short period, and concentration-dependent cytotoxicity was induced by degraded PE in all cell lines. Our results indicate that the cytotoxic effect of PE on different cell types depends on the degree of microplastic degradation, which contributes to our understanding of the effects of PE microplastics on humans.

First synthesis of acylated nitrocyclopropanes.

Although nitrocyclopropanedicarboxylic acid esters are widely used in organic syntheses, nitrocyclopropanes with an acyl group have not yet been synthesized. When adducts of ß-nitrostyrene and 1,3-dicarbonyl compounds are treated with (diacetoxyiodo)benzene and tetrabutylammonium iodide, iodination occurs at the α-position of the nitro group, and the subsequent O-attack of the enol moiety leads to 2,3-dihydrofuran. Cyclopropane was successfully synthesized through C-attack as the acyl group became bulkier. The obtained nitrocyclopropane was transformed into furan upon treatment with tin(II) chloride via a ring-opening/ring-closure process.

A new approach to 10-arylated 5H-dibenzo[b,f]azepines using syn-selective hydrohalogenation of ethynylaniline.

A new synthetic method for 10-arylated dibenzo[b,f]azepines was developed. The pseudo-intramolecular hydrohalogenation of 2-(2'-bromophenyl)ethynylaniline, which proceeded in a syn-selective manner without forming any detectable over-addition product, was a crucial step. All attempts of subsequent arylation via Suzuki-Miyaura cross coupling and construction of a seven membered ring via Ullmann-type intramolecular coupling were unsuccessful because of dehydrohalogenation or other side reactions. This problem was overcome by the N-acetylation of the amino group, which facilitated the abovementioned coupling reactions to afford the desired 10-arylated dibenzoazepines.

Development of a synthetic equivalent of α,α-dicationic acetic acid leading to unnatural amino acid derivatives via tetrafunctionalized methanes.

Diethyl mesoxalate (DEMO) exhibits high electrophilicity and accepts the nucleophilic addition of a less nucleophilic acid amide to afford N,O-hemiacetal. However, our research showed that elimination of the amide moiety proceeded more easily than dehydration upon treatment with a base. This problem was overcome by reacting DEMO with an acid amide in the presence of acetic anhydride to efficiently obtain N,O-acetal. Acetic acid was eliminated leading to the formation of N-acylimine in situ upon treatment with the base. N-Acylimine is also electrophilic, accepting the second nucleophilic addition by pyrrole or indole to form α,α-disubstituted malonates. Subsequent hydrolysis followed by decarboxylation resulted in (α-indolyl-α-acylamino)acetic acid formation; homologs of tryptophan. Through this process, DEMO serves as a synthetic equivalent of α,α-dicationic acetic acid to facilitate nucleophilic introduction of the two substituents.

Synthesis of Nitroaromatic Compounds via Three-Component Ring Transformations.

1-Methyl-3,5-dinitro-2-pyridone serves as an excellent substrate for nucleophilic-type ring transformation because of the electron deficiency and presence of a good leaving group. In this review, we focus on the three-component ring transformation (TCRT) of dinitropyridone involving a ketone and a nitrogen source. When dinitropyridone is allowed to react with a ketone in the presence of ammonia, TCRT proceeds to afford nitropyridines that are not easily produced by alternative procedures. Ammonium acetate can be used as a nitrogen source instead of ammonia to undergo the TCRT, leading to nitroanilines in addition to nitropyridines. In these reactions, dinitropyridone serves as a safe synthetic equivalent of unstable nitromalonaldehyde.

One-pot and metal-free synthesis of 3-arylated-4-nitrophenols via polyfunctionalized cyclohexanones from ß-nitrostyrenes.

ß-Nitrostyrenes underwent a Diels-Alder reaction with Danishefsky's diene to afford cyclohexenes together with the corresponding hydrolyzed products, 3-arylated-5-methoxy-4-nitrocyclohexanones. When the reaction was conducted in the presence of water, the cyclohexenes were efficiently hydrolyzed into cyclohexanones. Subsequent aromatization by heating the cyclohexanone with a catalytic amount of iodine in dimethyl sulfoxide gave 3-arylated-4-nitrophenols. The reaction of nitrostyrenes with Danishefsky's diene could be conducted in one pot to directly afford the corresponding nitrophenols. Moreover, a heteroaryl group, e.g., a thienyl group could be introduced into the nitrophenol framework.

Alkynylation and Cyanation of Alkenes Using Diverse Properties of a Nitro Group.

In the work being reported here, ß-nitrostyrenes bearing an ethoxycarbonyl group at the ß-position serve as scaffolds for the synthesis of α,ß-difunctionalized alkenes. Nitrocinnamates undergo Michael addition reactions with versatile sp3- and sp2-nucleophiles such as alcohols, Grignard reagents, alkylcopper, and dialkylzinc to afford ß-substituted nitroethane derivatives. However, various attempts to obtain a double bond via nitrous acid elimination failed because steric repulsion between the newly introduced sp3/sp2 substituent and the nitro group hampered the required anti-coplanar conformation. This problem was successfully overcome using a smaller sp-nucleophile such as lithium acetylide, potassium cyanide, or trimethylsilyl cyanide. While treatment of the adduct with a strong base did not lead to the elimination of nitrous acid, the weaker triethylamine efficiently afforded functionalized enynes and acrylonitriles in high yields.

Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors.

In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H2C═CH-Acc, 1) and styrenes (PhCH═CH-Acc, 2) with pyridinium ylides 3, sulfonium ylide 4, and sulfonyl-substituted chloromethyl anion 5. Substitution of the 57 measured second-order rate constants (log k) and the previously reported nucleophile-specific parameters N and sN for 3-5 into the correlation log k = sN(E + N) allowed us to calculate 15 new empirical electrophilicity parameters E for Michael acceptors 1 and 2. The use of the same parameters sN, N, and E for these different types of reactions shows that all reactions proceed via a common rate-determining step, the nucleophilic attack of 3-5 at the Michael acceptors with formation of acyclic intermediates, which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with 3) and cyclopropanes (with 4 and 5), respectively. The electrophilicity parameters E thus determined can be used to calculate the rates of the reactions of Michael acceptors 1 and 2 with any nucleophile of known N and sN. DFT calculations were performed to confirm the suggested reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities E correlate poorly with the LUMO energies and with Parr's electrophilicity index ω, good correlations were found between the experimentally observed electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities.

Synthesis of Functionalized 3-Cyanoisoxazoles Using a Dianionic Reagent.

A series of 5-acylated 3-cyanoisoxazoles were efficiently synthesized by the Michael addition of dianionic cyano-aci-nitroacetate to α-chloro-α,ß-unsaturated ketones followed by intramolecular nucleophilic substitution of the nitronate ion intermediate. In this process, the dianionic reagent serves as the safe synthetic equivalent of the explosive nitroacetonitrile. The 3-cyano group is sufficiently reactive toward ethanolysis and 1,3-dipolar cycloaddition with an azide to afford ethyl ester and tetrazole, respectively. A pyridine ring between the 5-acyl and the 4-aryl group was also constructed. This led to the formation of the isoxazolo[5,4-c]quinoline derivative.

A direct and vicinal functionalization of the 1-methyl-2-quinolone framework: 4-alkoxylation and 3-chlorination.

Bis(functionalization), 4-alkoxylation and 3-chlorination, of the 1-methyl-2-quinolone framework was achieved under mild conditions by a sequential treatment of 3-nitrated 1-methyl-2-quinolones with sodium alkoxide and N-chlorosuccinimide. Moreover, a succinimide group instead of an alkoxy group was introduced at the 4-position, affording a masked form of the 4-amino-3-chloro-2-quinolone derivative. Furthermore, the prepared vicinally functionalized quinolones thus obtained were subjected to a Suzuki-Miyaura coupling reaction, arylating the 3-position.

Synthesis of 6-substituted 2-phenacylpyridines from 2-(phenylethynyl)pyridine via isoxazolo[2,3-a]pyridinium salt.

When 2-(phenylethynyl)pyridine was oxidized, the formed N-oxide immediately cyclized at the ethynyl group to form isoxazolo[2,3-a]pyridinium salt. This salt underwent Reissert-Henze-type reactions with alcohol in the presence of a base to afford 6-substituted 2-phenacylpyridines, which are not easily synthesized through alternative procedures. When acetonitrile was used as a solvent, an amide functional group was introduced into the phenacylpyridine framework. Moreover, a hetero-atom at the 6-position facilitated the oxidation of the phenacyl group to afford α-diketones upon simple exposure of the reaction mixture to air.

Dual Behavior of Iodine Species in Condensation of Anilines and Vinyl Ethers Affording 2-Methylquinolines.

A metal-free, mild and efficient method for the synthesis of 2-methylquinolines was successfully developed by condensation of anilines with vinyl ethers in the presence of catalytic amount of iodine. Modification of both pyridine and benzene moieties was easily achieved by changing only the vinyl ether and aniline. In this reaction, the iodine species was revealed to show dual behavior; molecular iodine serves as an oxidant, while its reduced form, hydrogen iodide, activates the vinyl ether. The redox reaction between these iodine species enables the use of a catalytic amount of iodine in this synthetic method.

An Alternative Synthetic Approach to 3-Alkylated/Arylated 5-Nitropyridines.

An alternative method for the synthesis of 3-alkylated/arylated 5-nitropyridines was developed involving a three-component ring transformation of 3,5-dinitro-2-pyridone on treatment with aldehyde in the presence of ammonium acetate. This method facilitates the modification of the substituent at the 3-position by changing the precursor aldehyde. The use of solid ammonium acetate instead of ammonia as the nitrogen source renders the synthetic method more practical and user-friendly.

Development of variously functionalized nitrile oxides.

N-Methylated amides (N,4-dimethylbenzamide and N-methylcyclohexanecarboxamide) were systematically subjected to chemical transformations, namely, N-tosylation followed by nucleophilic substitution. The amide function was converted to the corresponding carboxylic acid, esters, amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3-functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and formyl moieties.

Metal-free α-hydroxylation of α-unsubstituted ß-oxoesters and ß-oxoamides.

A direct metal-free α-hydroxylation of α-unsubstituted ß-oxoesters and ß-oxoamides was developed using m-chloroperbenzoic acid as the oxidant. This transformation enabled straightforward metal-free access to important α-hydroxy-ß-dicarbonyl moieties under mild reaction conditions. Furthermore, the hydroxylated products were readily converted into vicinal tricarbonyl compounds, which are useful synthetic precursors of numerous biological targets.

Redox chemistry of nickel(II) complexes supported by a series of noninnocent ß-diketiminate ligands.

Nickel complexes of a series of ß-diketiminate ligands ((R)L(-), deprotonated form of 2-substituted N-[3-(phenylamino)allylidene]aniline derivatives (R)LH, R = Me, H, Br, CN, and NO2) have been synthesized and structurally characterized. One-electron oxidation of the neutral complexes [Ni(II)((R)L(-))2] by AgSbF6 or [Ru(III)(bpy)3](PF6)3 (bpy = 2,2'-bipyridine) gave the corresponding metastable cationic complexes, which exhibit an EPR spectrum due to a doublet species (S = 1/2) and a characteristic absorption band in near IR region ascribable to a ligand-to-ligand intervalence charge-transfer (LLIVCT) transition. DFT calculations have indicated that the divalent oxidation state of nickel ion (Ni(II)) is retained, whereas one of the ß-diketiminate ligands is oxidized to give formally a mixed-valence complex, [Ni(II)((R)L(-))((R)L(•))](+). Thus, the doublet spin state of the oxidized cationic complex can be explained by taking account of the antiferromagnetic interaction between the high-spin nickel(II) ion (S = 1) and the organic radical (S = 1/2) of supporting ligand. A single-crystal structure of one of the cationic complexes (R = H) has been successfully determined to show that both ligands in the cationic complex are structurally equivalent. On the basis of theoretical analysis of the LLIVCT band and DFT calculations as well as the crystal structure, the mixed-valence complexes have been assigned to Robin-Day class III species, where the radical spin is equally delocalized between the two ligands to give the cationic complex, which is best described as [Ni(II)((R)L(0.5•-))2](+). One-electron reduction of the neutral complexes with decamethylcobaltocene gave the anionic complexes when the ligand has the electron-withdrawing substituent (R = CN, NO2, Br). The generated anionic complexes exhibited EPR spectra due to a doublet species (S = 1/2) but showed no LLIVCT band in the near-IR region. Thus, the reduced complexes are best described as the d(9) nickel(I) complexes supported by two anionic ß-diketiminate ligands, [Ni(I)((R)L(-))2](-). This conclusion was also supported by DFT calculations. Substituent effects on the electronic structures of the three oxidation states (neutral, cationic, and anionic) of the complexes are systematically evaluated on the basis of DFT calculations.

Synthesis of Zwitterionic Phospholipid-Connected Silane Coupling Agents and Their Hybridization with Graphene Oxide.

The hybridization of lipids with graphene is expected to produce a promising, novel biomaterial. However, there are limited examples of the covalent introduction of lipid molecules, especially the immobilization of lipid molecules, onto graphene on a substrate. Therefore, we investigated the hybridization of a silane coupling agent having phospholipid moieties with graphene oxide on substrates prepared by photo-oxidation using chlorine dioxide. Three silane coupling agents with different carbon chain lengths (C4, C6, C8) were synthesized and phospholipid molecules were introduced onto graphene on a substrate. Phospholipid-immobilized graphene on a grid for TEM (transmission electron microscope) was used for EM analysis of proteins (glyceraldehyde 3-phosphate dehydrogenase and ß-galactosidase), enabling the observation of sufficient particles compared to the conventional graphene grid.

[Preparation of Degraded Microplastics That Imitate Surface Properties in the Environment].

Microplastics are small pieces of plastic that are less than 5 mm in length. These plastics have been detected in various environments, including the ocean, soil, and air. Their abundance have raised concerns regarding their potential effects on living organisms, including humans. The surface of microplastics degrades due to external factors such as ultraviolet rays and water waves in the environment. Therefore, assessing the biological impact of microplastics and considering their state of degradation is important. Among the physical properties of microplastics, we focused on the chemical degradation of microplastics. Specifically, we used vacuum ultraviolet (VUV) light to accelerate the degradation of polyethylene (PE) and prepared PE samples representing the degradation of PE to varying degrees. The surface properties of PE samples prepared using VUV were similar to those obtained from the environment. Cytotoxicity tests were then used to evaluate the effects of undegraded and degraded PE on cells. We found that the severity of cytotoxicity increased with the extent to which the PE would have been degraded, suggesting that the degree of degradation is strongly linked to the severity of the observed deleterious effects on living organisms. In conclusion, this finding contributes to our understanding of the effects of polyethylene microplastics on the human body.

[Mechanisms of Cell Toxicity Caused by Degraded Microplastics].

Microplastics (MPs), defined as plastic particles less than 5 mm in size, are ubiquitous in the environment. The accumulation of MPs in various environmental compartments, such as the ocean, soil, and air, has raised considerable concerns regarding their impact on ecological systems, including marine life and human health. Notably, MPs have been detected in marine organisms such as shellfish and fish, and have even been found in the human body, including in the blood and placenta. Moreover, considering that MPs have been detected in drinking water, human exposure to these particles in daily life is inevitable. To assess the risk posed by MPs to human health, it is essential to consider their physiological and chemical properties, including size, shape, surface modification, and material composition. However, current risk analyses focus primarily on spherical MPs with smooth surfaces, which differ substantially from most of the MPs detected in the environment. Environmental factors, such as ocean waves and ultraviolet radiation, alter the properties of MPs, including size, shape, and surface characteristics. In this review, we summarize current research on MPs, with a particular emphasis on the effects of MP degradation on human health. Furthermore, we generated MPs with surface degradation and evaluated their impact on cell toxicity, along with the underlying biological mechanisms.

Chiral recognition and kinetic resolution of aromatic amines via supramolecular chiral nanocapsules in nonpolar solvents.

Herein we report the first example of chiral recognition and kinetic resolution of aromatic amine guests using supramolecular nanocapsules assembled from cyclodextrin derivatives in nonpolar media. With these nanocapsules, an extremely high chiral recognition of 1-(1-naphthyl)ethylamine (1) in cyclohexane was achieved, with a binding selectivity of up to 41 for (S)-1 over (R)-1. In addition, kinetic resolution of 1 through enantioselective N-acylation was accomplished with an enantiomeric excess of up to 91%.