Chlorination of arenes via the degradation of toxic chlorophenols.

Aryl chlorides are among the most versatile synthetic precursors, and yet inexpensive and benign chlorination techniques to produce them are underdeveloped. We propose a process to generate aryl chlorides by chloro-group transfer from chlorophenol pollutants to arenes during their mineralization, catalyzed by Cu(NO3)2/NaNO3 under aerobic conditions. A wide range of arene substrates have been chlorinated using this process. Mechanistic studies show that the Cu catalyst acts in cooperation with NOx species generated from the decomposition of NaNO3 to regulate the formation of chlorine radicals that mediate the chlorination of arenes together with the mineralization of chlorophenol. The selective formation of aryl chlorides with the concomitant degradation of toxic chlorophenol pollutants represents a new approach in environmental pollutant detoxication. A reduction in the use of traditional chlorination reagents provides another (indirect) benefit of this procedure.

Organophotocatalytic selective deuterodehalogenation of aryl or alkyl chlorides.

Development of practical deuteration reactions is highly valuable for organic synthesis, analytic chemistry and pharmaceutic chemistry. Deuterodehalogenation of organic chlorides tends to be an attractive strategy but remains a challenging task. We here develop a photocatalytic system consisting of an aryl-amine photocatalyst and a disulfide co-catalyst in the presence of sodium formate as an electron and hydrogen donor. Accordingly, many aryl chlorides, alkyl chlorides, and other halides are converted to deuterated products at room temperature in air (>90 examples, up to 99% D-incorporation). The mechanistic studies reveal that the aryl amine serves as reducing photoredox catalyst to initiate cleavage of the C-Cl bond, at the same time as energy transfer catalyst to induce homolysis of the disulfide for consequent deuterium transfer process. This economic and environmentally-friendly method can be used for site-selective D-labeling of a number of bioactive molecules and direct H/D exchange of some drug molecules.

Synthesis of 4-(3-oxo-3-phenylpropyl)morpholin-4-ium chloride analogues and their inhibitory activities of nitric oxide production in lipopolysaccharide-induced BV2 cells.

Based on our previous report that 3-morpholino-1-phenylpropan-1-one 2, one of the fluoxetine's simplified morpholino analogue, inhibited nitric oxide (NO) production, in this paper, various substituted benzene analogues with morpholine hydrochloride of 2 were synthesized and their inhibitory effects on NO production in lipopolysaccharide (LPS)-induced BV2 cells were tested. Among the synthesized compounds, 2-trifluoromethyl analogue 16n (IC50 = 8.6 µM) showed a significantly higher inhibitory activity than that of the parent compound 2a (IC50 > 50 µM) and suppressed NO production dose-dependently without cytotoxicity. Compound 16n also inhibited iNOS expression in LPS-induced BV2 cells at 2, 10 and 20 µM concentrations. These results suggest that compound 16n inhibited NO production by suppressing the expression of iNOS and can be used as a lead structure for developing new inhibitor of NO production.

Efficient synthesis of amino acids capped gold nanoparticles from easily reducible aryldiazonium tetrachloroaurate(III) salts for cellular uptake study.

Biomimetic synthesis of gold nanoparticles (GNPs) is critical in biomedical applications. Gold bioconjugates were fabricated by capping the water-dispersible gold-carbon nanoparticles with tyrosine, tryptophan and cysteine amino acids. Incubation of the water-soluble and easily reducible aryldiazonium gold(III) salt [HOOC-4-C6H4N≡N]AuCl4 with amino acids at room temperature formed a purple color over a few minutes with tryptophan and tyrosine and over two hours with cysteine. Rarely that cysteine is capable of reducing gold(III) precursors; however, a cysteine capped gold bioconjugate was synthesized and characterized in this study. Capping GNPs with amino acids was confirmed by high resolution transmission electron microscopy (TEM) and agarose gel electrophoresis. Depending on the amino acid, synthesized particles size was 27.2 ± 5.4 nm, 14.6 ± 7.7 nm and 8.6 ± 2.6 nm for tyrosine, tryptophan and cysteine, respectively. The amino acids capped GNPs showed negligible cytotoxicity to human dermal normal fibroblast cell lines. The highly water dispersible bioconjugates were studied for in vitro cellular uptake by HeLa cancer cells using confocal laser scan microscopy (CLSM) after being labelled with FITC (GNPs-COOH-FITC) and the nuclei were counter stained with DAPI fluorescent dyes. The biomimetic route for the synthesis of the amino acids reduced gold-carbon nanoparticles will benefit the applications in biomedical devices and biosensors.

Synthesis of Glycosyl Chlorides and Bromides by Chelation Assisted Activation of Picolinic Esters under Mild Neutral Conditions.

A general method has been developed for the formation of glycosyl chlorides and bromides from picolinic esters under mild and neutral conditions. Benchtop stable picolinic esters are activated by a copper(II) halide species to afford the corresponding products in high yields with a traceless leaving group. Rare ß glycosyl chlorides are accessible via this route through neighboring group participation. Additionally, glycosyl chlorides with labile protecting groups previously not easily accessible can be prepared.

Plasmonic microgels of Au nanorods: Self-assembly and applications in chemophotothermo-synergistic cancer therapy.

Plasmonic microgels (PMgels) of the self-assembled gold nanorods (Au NRs) with side-by-side piles in ionic liquid microgels were prepared. Transmission electron microscopy (TEM) images revealed unique self-growth and self-arrangement of Au NRs in the microgel systems. The fabrication of PMgels occurs through co-assembling Au NRs and an ionic liquid microgel system, therefore differs from the fabrication of conventional plasmonic hybrid nanocomposites. These PMgels showed strong absorption in the near-infrared window and enhanced photothermal conversion efficiency, up to 52.8%, compared to the Au NRs (22%) as a result of the ordering and dense packing of Au NRs in the microgels. When the PMgels were exposed to a near-IR laser, the doxorubicin hydrochloride (Dox) released from PMgels and the resulting thermal effect can immensely inhibit tumor growth both in vitro and in vivo. The tests demonstrated that no tumor metastasis occurred. This platform of the PMgels with the laser-controlled delivery system could provide chemo-photothermal synergistic therapy for a wide spectrum of diseases.

Water, Ions, and Hemoglobin: Effects on Allostery and Polymerization.

Proteins that function in aqueous solution can be perturbed by the solvent. Here we present experimental studies on two such interactions in the hemoglobin molecule. (1) Hemoglobin's oxygen binding is altered by introduction of crowding species or osmoticants, such as sucrose, through the linked binding of ions such as Cl or CO2, but not otherwise. This rules out a significant role of buried surface in the allosteric energetics. (2) Sickle hemoglobin (HbS) polymerizes more readily in high concentrations of phosphate buffer. Such polymerization is analyzed quantitatively here for the first time in terms of the double nucleation mechanism. The changes in solubility are found to account for the increase in monomer addition rates and nucleation rates without requiring additional parameter adjustments. In the analysis, we also show how the analytical formulation of HbS nucleation may be adapted to include water that occupies the interstices between the assembled molecules. While such a "correction" has been applied to the equilibrium process, it has not previously been applied to the nucleation process.

Stable-carbon isotope ratios for sourcing the nerve-agent precursor methylphosphonic dichloride and its products.

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ13C analysis to be used as a fingerprinting tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. We demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.

A carbon tetrachloride-free synthesis of N-phenyltrifluoroacetimidoyl chloride.

N-Phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) is a reagent widely used for the preparation of glycosyl N-phenyltrifluoroacetimidates. However, the most commonly applied method requires carbon tetrachloride, a hepatotoxic reagent that has been phased out under the Montreal Protocol. We report a new synthesis of N-phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) using dichlorotriphenylphosphane and triethylamine.

Palladium-catalysed synthesis of triaryl(heteroaryl)methanes.

Tetraarylmethane derivatives are desirable for a variety of applications, but difficult to access with modern C-C bond-forming reactions. Here we report a straightforward method for palladium-catalysed arylation of aryl(heteroaryl)methanes and diaryl(heteroaryl)methanes with aryl chlorides. This reaction enables introduction of various aryl groups to construct triaryl(heteroaryl)methanes via a C-H functionalization in good to excellent yield, and represents the first step towards a general transition metal catalysed synthesis of tetraarylmethanes.

Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis.

Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules.

A Simple Method for the Size Controlled Synthesis of Stable Oligomeric Clusters of Gold Nanoparticles under Ambient Conditions.

Reducing dilute aqueous HAuCl4 with sodium thiocyanate (NaSCN) under alkaline conditions produces 2 to 3 nm diameter nanoparticles. Stable grape-like oligomeric clusters of these yellow nanoparticles of narrow size distribution are synthesized under ambient conditions via two methods. The delay-time method controls the number of subunits in the oligoclusters by varying the time between the addition of HAuCl4 to alkaline solution and the subsequent addition of reducing agent, NaSCN. The yellow oligoclusters produced range in size from ~3 to ~25 nm. This size range can be further extended by an add-on method utilizing hydroxylated gold chloride (Na(+)[Au(OH4-x)Clx](-)) to auto-catalytically increase the number of subunits in the as-synthesized oligocluster nanoparticles, providing a total range of 3 nm to 70 nm. The crude oligocluster preparations display narrow size distributions and do not require further fractionation for most purposes. The oligoclusters formed can be concentrated >300 fold without aggregation and the crude reaction mixtures remain stable for weeks without further processing. Because these oligomeric clusters can be concentrated before derivatization they allow expensive derivatizing agents to be used economically. In addition, we present two models by which predictions of particle size can be made with great accuracy.

Synthesis of diverse pyrazole-4-sulfonyl chlorides starting from 2-(benzylthio)malonaldehyde.

A series of pyrazole-4-sulfonyl chlorides was obtained by a convenient 2-step method starting from synthetically available 2-(benzylthio)malonaldehyde. The method can be applied for the effective multi-gram synthesis of diverse pyrazole-containing sulfonyl chlorides which are mostly not available by other methods.

Labile ruthenium(ii) complexes with extended phenyl-substituted terpyridyl ligands: synthesis, aquation and anticancer evaluation.

Ruthenium complexes have been considered as promising substitutes for cisplatin in cancer chemotherapy. However, novel ruthenium-based therapies are faced with some limitations, such as unimpressive cytotoxicity toward solid tumors. Herein, we designed and synthesized phenyl-substituted terpyridyl ruthenium(ii) complexes ([Ru(tpy)(bpy)Cl](+) (Ru1), [Ru(phtpy)(bpy)Cl](+) (Ru2) and [Ru(biphtpy)(bpy)Cl](+) (Ru3)) which exhibited distinctly different anticancer activity. Ru1-Ru3 all underwent moderate aquation in buffer solution and this process was significantly inhibited by high chloride concentration. Cancer cells were found to readily uptake the relatively hydrophobic Ru3, as quantified using inductively coupled plasma mass spectrometry (ICP-MS). Ru1 was found to be non-cytotoxic (IC50 > 100 µM) while Ru3 exhibited very promising cytotoxicity on both two-dimensional (2D) cancer cell monolayers and 3D MCTSs. An antiproliferative assay revealed that Ru3 significantly inhibited cellular DNA replication which ultimately induced apoptosis of cancer cells.

Preparation of Furo[3,2-c]coumarins from 3-Cinnamoyl-4-hydroxy-2H-chromen-2-ones and Acyl Chlorides: A Bu3P-Mediated C-Acylation/Cyclization Sequence.

A Bu3P-mediated cyclization reaction of 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones though electrophilic addition of acyl chlorides towards the synthesis of highly functionalized furo[3,2-c]coumarins bearing a phosphorus ylide moiety is described. These unprecedented cyclization reaction proceeds under mild reaction conditions within short reaction times (1 min to 1 h), and can be further applied in the synthesis of alkenyl-substituted furo[3,2-c]coumarins by the treatment with carbonyl electrophiles under basic conditions.

Synthesis, characterization and theoretical calculations of (1,2-diaminocyclohexane)(1,3-diaminopropane)gold(III) chloride complexes: in vitro cytotoxic evaluations against human cancer cell lines.

The gold(III) complexes of the type (1,2-diaminocyclohexane)(1,3-diaminopropane)gold(III) chloride, [(DACH)Au(pn)]Cl3, [where DACH = cis-, trans-1,2- and S,S-1,2-diaminocyclohexane and pn = 1,3-diaminopropane] have been synthesized and characterized using various spectroscopic and analytical techniques including elemental analysis, UV-Vis and FTIR spectroscopy; solution as well as solid-state NMR measurements. The solid-state (13)C NMR shows that 1,2-diaminocyclohexane (1,2-DACH) and 1,3-diaminopropane (pn) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was checked by UV-Vis spectroscopy and NMR measurements. The molecular structure of compound 1 (containing cis-1,2-DACH) was determined by X-ray diffraction analysis. The structure of 1 consists of [(cis-DACH)Au(pn)](3+) complex ion and chloride counter ions. Each gold atom in the complex ion adopts a distorted square-planar geometry. The structural details and relative stabilities of the four possible isomers of the complexes were also estimated at the B3LYP/LANL2DZ level of theoretical calculations. The computational study demonstrates that trans- conformations are slightly more stable than the cis- conformations. The antiproliferative effects and cytotoxic properties of the mixed ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 3 (containing 1S,2S-(+)-1,2-(DACH)) is the most effective antiproliferative agent. The IC50 data reveal that the in vitro cytotoxicity of complex 3 against SGC7901 cancer cells manifested similar and very pronounced cytotoxic effects with respect to cisplatin. Moreover, the electrochemical behavior, and the interaction of complex 3 with two well-known model proteins, namely, hen egg white lysozyme and bovine serum albumin is also reported.

Synthesis of 1,3,5-triazines via Cu(OAc)2-catalyzed aerobic oxidative coupling of alcohols and amidine hydrochlorides.

Cu(OAc)2 was found to be an efficient catalyst for dehydrogenative synthesis of 1,3,5-triazine derivatives via oxidative coupling reaction of amidine hydrochlorides and alcohols in air. Both aromatic and aliphatic alcohols can be involved in the reaction and thirty-three products were obtained with good to excellent yields. Moreover, the use of a ligand, strong base and organic oxidant is unnecessary.

Synthesis of Carboxylate Cp*Zr(IV) Species: Toward the Formation of Novel Metallocavitands.

With the intent of generating metallocavitands isostructural to species [(CpZr)3(µ(3)-O)(µ(2)-OH)3(κO,O,µ(2)-O2C(R))3](+), the reaction of Cp*2ZrCl2 and Cp*ZrCl3 with phenylcarboxylic acids was carried out. Depending on the reaction conditions, five new complexes were obtained, which consisted of Cp*2ZrCl(κ(2)-OOCPh) (1), (Cp*ZrCl(κ(2)-OOCPh))2(µ-κ(2)-OOCPh)2 (2), [(Cp*Zr(κ(2)-OOCPh))2(µ-κ(2)-OOCPh)2(µ(2)-OH)2]·Et2O (3·Et2O), [[Cp*ZrCl2](µ-Cl)(µ-OH)(µ-O2CC6H5)[Cp*Zr]]2(µ-O2CC6H5)2 (4), and [Cp*ZrCl4][(Cp*Zr)3(κ2-OOC(C6H4Br)3(µ3-O)(µ2-Cl)2(µ2-OH)] [5](+)[Cp*ZrCl4](-). The structural characterization of the five complexes was carried out. Species 3·Et2O exhibits host-guest properties where the diethyl ether molecule is included in a cavity formed by two carboxylate moieties. The secondary interactions between the cavity and the diethyl ether molecule affect the structural parameters of the complex, as demonstrated be the comparison of the density functional theory models for 3 and 3·Et2O. Species 5 was shown to be isostructural to the [(CpZr)3(µ(3)-O)(µ(2)-OH)3(κO,O,µ(2)-O2C(R))3](+) metallocavitands.

Synthesis of phosphinoferrocene amides and thioamides from carbamoyl chlorides and the structural chemistry of Group 11 metal complexes with these mixed-donor ligands.

The reaction of in situ generated 1'-(diphenylphosphino)-1-lithioferrocene with carbamoyl chlorides, ClC(E)NMe2, affords the corresponding (thio)amides, Ph2PfcC(E)NMe2 (E = O (), S (); fc = ferrocene-1,1'-diyl). These compounds as well as their analogues, Ph2PfcC(O)NHMe () and Ph2PfcC(O)NH2 (), prepared from 1'-(diphenylphosphino)ferrocene-1-carboxylic acid (Hdpf) were studied as ligands for the Group 11 metal ions. In the reactions with [Cu(MeCN)4][BF4], the amides give rise to bis-chelate complexes of the type [Cu(L-κ(2)O,P)2][BF4]. Similar products, [Ag(L-κ(2)O,P)2]ClO4, are obtained from silver(i) perchlorate and , or . In contrast, the reaction of AgClO4 with produces a unique molecular dimer [Ag()(ClO4-κO)]2, where the metal centres are bridged by the sulfur atoms of the P,S-chelating thioamides. The reactions of with [AuCl(tht)] (tht = tetrahydrothiophene) afford the expected gold(i)-phosphine complexes, [AuCl(L-κP)], containing uncoordinated (thio)amide moieties. Hemilabile coordination of the phosphinoamide ligands in complexes with the soft Group 11 metal ions is established by the crystal structure of a solvento complex, [Cu(-κ(2)O,P)(-κP)(CHCl3-κCl)][BF4], which was isolated serendipitously during an attempted crystallisation of [Cu(-κ(2)O,P)2][BF4]. All of the compounds are characterised by spectroscopic methods, and the structures of several representatives of both the free phosphinoamides and their complexes are determined by X-ray diffraction analysis and further studied by DFT calculations and cyclic voltammetry.