Electrochemical Synthesis of Gold-N-Heterocyclic Carbene Complexes.

An electrochemical synthesis of gold(I)-N-heterocyclic carbene (Au-NHC) complexes has been developed. The electrochemical methodology uses only imidazolium salts, gold metal electrodes, and electricity to produce these complexes with hydrogen gas as the only by-product. This high-yielding and operationally simple procedure has been used to produce eight mononuclear and three dinuclear Au-NHC complexes. The electrochemical procedure facilitates a clean reaction with no by-products. As such, Au-NHC complexes can be directly transferred to catalytic reactions without work-up or purification. The Au-NHC complexes were produced on-demand and tested as catalysts in a vinylcyclopropanation reaction. All mononuclear Au-NHC complexes performed similarly to or better than the isolated complexes.

Modification of Polysulfide Surfaces with Low-Power Lasers.

The modification of polymer surfaces using laser light is important for many applications in the nano-, bio- and chemical sciences. Such capabilities have supported advances in biomedical devices, electronics, information storage, microfluidics, and other applications. In most cases, these modifications require high power lasers that are expensive and require specialized equipment and facilities to minimize risk of hazardous radiation. Additionally, polymer systems that can be easily modified by lasers are often complex and costly to prepare. In this report, these challenges are addressed with the discovery of low-cost sulfur copolymers that can be rapidly modified with lasers emitting low-power infrared and visible light. The featured copolymers are made from elemental sulfur and either cyclopentadiene or dicyclopentadiene. Using a suite of lasers with discreet wavelengths (532, 638 and 786 nm) and powers, a variety of surface modifications could be made on the polymers such as controlled swelling or etching via ablation. The facile synthesis and laser modification of these polymer systems were exploited in applications such as direct laser lithography and erasable information storage.

Electrochemical Synthesis of Poly(trisulfides).

With increasing interest in high sulfur content polymers, there is a need to develop new methods for their synthesis that feature improved safety and control of structure. In this report, electrochemically initiated ring-opening polymerization of norbornene-based cyclic trisulfide monomers delivered well-defined, linear poly(trisulfides), which were solution processable. Electrochemistry provided a controlled initiation step that obviates the need for hazardous chemical initiators. The high temperatures required for inverse vulcanization are also avoided resulting in an improved safety profile. Density functional theory calculations revealed a reversible "self-correcting" mechanism that ensures trisulfide linkages between monomer units. This control over sulfur rank is a new benchmark for high sulfur content polymers and creates opportunities to better understand the effects of sulfur rank on polymer properties. Thermogravimetric analysis coupled with mass spectrometry revealed the ability to recycle the polymer to the cyclic trisulfide monomer by thermal depolymerization. The featured poly(trisulfide) is an effective gold sorbent, with potential applications in mining and electronic waste recycling. A water-soluble poly(trisulfide) containing a carboxylic acid group was also produced and found to be effective in the binding and recovery of copper from aqueous media.

Modelling mercury sorption of a polysulfide coating made from sulfur and limonene.

A polymer made from sulfur and limonene was used to coat silica gel and then evaluated as a mercury sorbent. A kinetic model of mercury uptake was established for a range of pH values and concentrations of sodium chloride. Mercury uptake was generally rapid from pH = 3 to pH = 11. At neutral pH, the sorbent (500 mg with a 10 : 1 ratio of silica to polymer) could remove 90% of mercury within one minute from a 100 mL solution containing 5 ppm HgCl2 and 99% over 5 minutes. It was found that sodium chloride, at concentrations comparable to seawater, dramatically reduced mercury uptake rates and capacity. It was also found that the spent sorbent was stable in acidic and neutral media, but degraded at pH 11 which led to mercury leaching. These results help define the conditions under which the sorbent could be used, which is an important advance for using this material in remediation processes.

Integration of the Exogenous Tuning of Thraustochytrid Fermentation and Sulfur Polymerization of Single-Cell Oil for Developing Plant-like Oils.

In this study, we have demonstrated a bioprocessing approach encompassing the exogenous addition of low-molecular-weight compounds to tune the fatty acid (FA) profile in a novel thraustochytrid strain to produce desirable FAs. Maximum lipid recovery (38%, dry wt. biomass) was obtained at 1% Tween 80 and 0.25 mg/L of Vitamin B12. The transesterified lipid showed palmitic acid (C16, 35.7% TFA), stearic acid (C18, 2.1% TFA), and oleic acid (C18:1, 18.7% TFA) as the main components of total FAs, which are mainly present in plant oils. Strikingly, D-limonene addition in the fermentation medium repressed the production of polyunsaturated fatty acid (PUFAs). Sulfur-polymerization-guided lipid separation revealed the presence of saturated (SFAs, 53% TFA) and monounsaturated fatty acids (MUFAs, 46.6% TFA) in thraustochytrid oil that mimics plant-oil-like FA profiles. This work is industrially valuable and advocates the use of sulfur polymerization for preparation of plant-like oils through tuneable thraustochytrid lipids.

Proteome-Wide Survey of Cysteine Oxidation by Using a Norbornene Probe.

Rapid detection of cysteine oxidation in living cells is critical in advancing our understanding of responses to reactive oxygen species (ROS) and oxidative stress. Accordingly, there is a need to develop chemical probes that facilitate proteome-wide detection of cysteine's many oxidation states. Herein, we report the first whole-cell proteomics analysis using a norbornene probe to detect the initial product of cysteine oxidation: cysteine sulfenic acid. The oxidised proteins identified in the HeLa cell model represent the first targets of the ROS hydrogen peroxide. The panel of protein hits provides new and important information about the targets of oxidative stress, including 148 new protein members of the sulfenome. These findings provide new leads for the study and understanding of redox signalling and diseases associated with oxidative stress.

Reactive Compression Molding Post-Inverse Vulcanization: A Method to Assemble, Recycle, and Repurpose Sulfur Polymers and Composites.

Inverse vulcanization provides dynamic and responsive materials made from elemental sulfur and unsaturated cross-linkers. These polymers have been used in a variety of applications such as energy storage, infrared optics, repairable materials, environmental remediation, and precision fertilizers. In spite of these advances, there is a need for methods to recycle and reprocess these polymers. In this study, polymers prepared by inverse vulcanization are shown to undergo reactive compression molding. In this process, the reactive interfaces of sulfur polymers are brought into contact by mechanical compression. Upon heating these molds at relatively low temperatures (≈100 °C), chemical bonding occurs at the polymer interfaces by S-S metathesis. This method of processing is distinct from previous studies on inverse vulcanization because the polymers examined in this study do not form a liquid phase when heated. Neither compression nor heating alone was sufficient to mold these polymers into new architectures, so this is a new concept in the manipulation of sulfur polymers. Additionally, high-level ab initio calculations revealed that the weakest S-S bond in organic polysulfides decreases linearly in strength from a sulfur rank of 2 to 4, but then remains constant at about 100 kJ mol-1 for higher sulfur rank. This is critical information in engineering these polymers for S-S metathesis. Guided by this insight, polymer repair, recycling, and repurposing into new composites was demonstrated.

Crosslinker Copolymerization for Property Control in Inverse Vulcanization.

Sulfur is an underused by-product of the petrochemicals industry. Recent research into inverse vulcanization has shown how this excess sulfur can be transformed into functional polymers, by stabilization with organic crosslinkers. For these interesting new materials to realize their potential for applications, more understanding and control of their physical properties is needed. Here we report four new terpolymers prepared from sulfur and two distinct alkene monomers that can be predictively tuned in glass transition, molecular weight, solubility, mechanical properties, and color.

Sulfur polymer composites as controlled-release fertilisers.

Sulfur polymer composites were prepared by the reaction of canola oil and elemental sulfur in the presence of the NPK fertiliser components ammonium sulfate, calcium hydrogen phosphate, and potassium chloride. These composites released nutrients in a controlled fashion, resulting in less wasted fertiliser and better health for potted tomato plants when compared to free NPK.

Chemical methods for mapping cysteine oxidation.

Cysteine residues in proteins are subject to diverse redox chemistry. Oxidation of cysteine to S-nitrosocysteine, cysteine sulfenic and sulfinic acids, disulfides and persulfides are a few prominent examples of these oxidative post-translational modifications. In living organisms, these modifications often play key roles in cell signalling and protein function, but a full account of this biochemistry is far from complete. It is therefore an important goal in chemical biology to identify what proteins are subjected to these modifications and understand their physiological function. This review provides an overview of these modifications, how they can be detected and quantified using chemical probes, and how this information provides insight into their role in biology. This survey also highlights future opportunities in the study of cysteine redox chemistry, the challenges that await chemists and biologists in this area of study, and how meeting such challenges might reveal valuable information for biomedical science.

Chemo- and Regioselective Lysine Modification on Native Proteins.

Site-selective chemical conjugation of synthetic molecules to proteins expands their functional and therapeutic capacity. Current protein modification methods, based on synthetic and biochemical technologies, can achieve site selectivity, but these techniques often require extensive sequence engineering or are restricted to the N- or C-terminus. Here we show the computer-assisted design of sulfonyl acrylate reagents for the modification of a single lysine residue on native protein sequences. This feature of the designed sulfonyl acrylates, together with the innate and subtle reactivity differences conferred by the unique local microenvironment surrounding each lysine, contribute to the observed regioselectivity of the reaction. Moreover, this site selectivity was predicted computationally, where the lysine with the lowest p Ka was the kinetically favored residue at slightly basic pH. Chemoselectivity was also observed as the reagent reacted preferentially at lysine, even in those cases when other nucleophilic residues such as cysteine were present. The reaction is fast and proceeds using a single molar equivalent of the sulfonyl acrylate reagent under biocompatible conditions (37 °C, pH 8.0). This technology was demonstrated by the quantitative and irreversible modification of five different proteins including the clinically used therapeutic antibody Trastuzumab without prior sequence engineering. Importantly, their native secondary structure and functionality is retained after the modification. This regioselective lysine modification method allows for further bioconjugation through aza-Michael addition to the acrylate electrophile that is generated by spontaneous elimination of methanesulfinic acid upon lysine labeling. We showed that a protein-antibody conjugate bearing a site-specifically installed fluorophore at lysine could be used for selective imaging of apoptotic cells and detection of Her2+ cells, respectively. This simple, robust method does not require genetic engineering and may be generally used for accessing diverse, well-defined protein conjugates for basic biology and therapeutic studies.

The Mercury Problem in Artisanal and Small-Scale Gold Mining.

Mercury-dependent artisanal and small-scale gold mining (ASGM) is the largest source of mercury pollution on Earth. In this practice, elemental mercury is used to extract gold from ore as an amalgam. The amalgam is typically isolated by hand and then heated-often with a torch or over a stove-to distill the mercury and isolate the gold. Mercury release from tailings and vaporized mercury exceed 1000 tonnes each year from ASGM. The health effects on the miners are dire, with inhaled mercury leading to neurological damage and other health issues. The communities near these mines are also affected due to mercury contamination of water and soil and subsequent accumulation in food staples, such as fish-a major source of dietary protein in many ASGM regions. The risks to children are also substantial, with mercury emissions from ASGM resulting in both physical and mental disabilities and compromised development. Between 10 and 19 million people use mercury to mine for gold in more than 70 countries, making mercury pollution from ASGM a global issue. With the Minamata Convention on Mercury entering force this year, there is political motivation to help overcome the problem of mercury in ASGM. In this effort, chemists can play a central role. Here, the problem of mercury in ASGM is reviewed with a discussion on how the chemistry community can contribute solutions. Introducing portable and low-cost mercury sensors, inexpensive and scalable remediation technologies, novel methods to prevent mercury uptake in fish and food crops, and efficient and easy-to-use mercury-free mining techniques are all ways in which the chemistry community can help. To meet these challenges, it is critical that new technologies or techniques are low-cost and adaptable to the remote and under-resourced areas in which ASGM is most common. The problem of mercury pollution in ASGM is inherently a chemistry problem. We therefore encourage the chemistry community to consider and address this issue that affects the health of millions of people.

Laying Waste to Mercury: Inexpensive Sorbents Made from Sulfur and Recycled Cooking Oils.

Mercury pollution threatens the environment and human health across the globe. This neurotoxic substance is encountered in artisanal gold mining, coal combustion, oil and gas refining, waste incineration, chloralkali plant operation, metallurgy, and areas of agriculture in which mercury-rich fungicides are used. Thousands of tonnes of mercury are emitted annually through these activities. With the Minamata Convention on Mercury entering force this year, increasing regulation of mercury pollution is imminent. It is therefore critical to provide inexpensive and scalable mercury sorbents. The research herein addresses this need by introducing low-cost mercury sorbents made solely from sulfur and unsaturated cooking oils. A porous version of the polymer was prepared by simply synthesising the polymer in the presence of a sodium chloride porogen. The resulting material is a rubber that captures liquid mercury metal, mercury vapour, inorganic mercury bound to organic matter, and highly toxic alkylmercury compounds. Mercury removal from air, water and soil was demonstrated. Because sulfur is a by-product of petroleum refining and spent cooking oils from the food industry are suitable starting materials, these mercury-capturing polymers can be synthesised entirely from waste and supplied on multi-kilogram scales. This study is therefore an advance in waste valorisation and environmental chemistry.

Sulfur-Limonene Polysulfide: A Material Synthesized Entirely from Industrial By-Products and Its Use in Removing Toxic Metals from Water and Soil.

A polysulfide material was synthesized by the direct reaction of sulfur and d-limonene, by-products of the petroleum and citrus industries, respectively. The resulting material was processed into functional coatings or molded into solid devices for the removal of palladium and mercury salts from water and soil. The binding of mercury(II) to the sulfur-limonene polysulfide resulted in a color change. These properties motivate application in next-generation environmental remediation and mercury sensing.

Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine.

Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80 seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.

Halide inhibition of the copper-catalysed azide-alkyne cycloaddition.

Chloride, bromide and iodide are inhibitors of the copper-catalysed azide-alkyne cycloaddition, with iodide exhibiting the most detrimental effects on rates and yields. A study of this inhibition is presented, along with experimental protocols to accommodate the presence of halides in this widely used reaction.

Melamine and melamine-formaldehyde polymers as ligands for palladium and application to Suzuki-Miyaura cross-coupling reactions in sustainable solvents.

The Suzuki-Miyaura cross-coupling reaction is a foundation stone of modern organic synthesis, as evidenced by its widespread use in the preparation of pharmaceuticals, agrochemicals, polymers, and other functional materials. With the prevalence of this venerable reaction in industrial synthesis, it is prudent to ensure its application adheres to the tenets of green chemistry. The introduction of cross-coupling catalysts that are active in sustainable solvents is therefore an important endeavor. In this report, a melamine-palladium complex is introduced as a versatile catalyst for the Suzuki-Miyaura cross-coupling reaction. This catalyst is soluble and active in both water and the renewable organic solvent ethyl lactate. The melamine-palladium catalyst can also be cross-linked by reaction with formaldehyde to generate an insoluble polymeric catalyst that can be recovered after the cross-coupling. The melamine-palladium system is inexpensive, easy to handle, bench-stable, and effective in catalysis in the presence of a variety of impurities (high cross-coupling yields were obtained in reactions run in unfiltered river water to illustrate this final point). Additionally, investigations reported herein revealed an intriguing relationship between catalytic efficiency and the base employed in the cross-coupling reaction. Implications for the mechanism of transmetalation in aqueous Suzuki-Miyaura cross-coupling reaction are discussed.

Inactivation of human coronaviruses using an automated room disinfection device.

The emergence of more virulent and epidemic strains of viruses, especially in the context of COVID-19, makes it more important than ever to improve methods of decontamination. The objective of this study was to evaluate the potential of on-demand production of chlorine species to inactivate human coronaviruses. The commercial prototype disinfection unit was provided by Unipolar Water Technologies. The Unipolar device generates active chlorine species using an electrochemical reaction and dispenses the disinfectant vapour onto surfaces with an aspirator. The minimum effective concentration and exposure time of disinfectant were evaluated on human hepatoma (Huh7) cells using 50% tissue culture infectious dose (TCID50) assay and human coronavirus 229E (HCoV-229E), a surrogate for pathogenic human coronaviruses. We showed that chlorine species generated in the Unipolar device inactivate HCoV-229E on glass surfaces at ≥ 400 parts per million active chlorine concentration with a 5 min exposure time. Here, inactivation refers to the inability of the virus to infect the Huh7 cells. Importantly, no toxic effect was observed on Huh7 cells for any of the active chlorine concentrations and contact times tested.

A "tag-and-modify" approach to site-selective protein modification.

Covalent modification can expand a protein's functional capacity. Fluorescent or radioactive labeling, for instance, allows imaging of a protein in real time. Labeling with an affinity probe enables isolation of target proteins and other interacting molecules. At the other end of this functional spectrum, protein structures can be naturally altered by enzymatic action. Protein-protein interactions, genetic regulation, and a range of cellular processes are under the purview of these post-translational modifications. The ability of protein chemists to install these covalent additions selectively has been critical for elucidating their roles in biology. Frequently the transformations must be applied in a site-specific manner, which demands the most selective chemistry. In this Account, we discuss the development and application of such chemistry in our laboratory. A centerpiece of our strategy is a "tag-and-modify" approach, which entails sequential installation of a uniquely reactive chemical group into the protein (the "tag") and the selective or specific modification of this group. The chemical tag can be a natural or unnatural amino acid residue. Of the natural residues, cysteine is the most widely used as a tag. Early work in our program focused on selective disulfide formation in the synthesis of glycoproteins. For certain applications, the susceptibility of disulfides to reduction was a limitation and prompted the development of several methods for the synthesis of more stable thioether modifications. The desulfurization of disulfides and conjugate addition to dehydroalanine are two routes to these modifications. The dehydroalanine tag has since proven useful as a general precursor to many modifications after conjugate addition of various nucleophiles; phosphorylated, glycosylated, peptidylated, prenylated, and even mimics of methylated and acetylated lysine-containing proteins are all accessible from dehydroalanine. While cysteine is a useful tag for selective modification, unnatural residues present the opportunity for bio-orthogonal chemistry. Azide-, arylhalide-, alkyne-, and alkene-containing amino acids can be incorporated into proteins genetically and can be specifically modified through various transformations. These transformations often rely on metal catalysis. The Cu-catalyzed azide-alkyne addition, Ru-catalyzed olefin metathesis, and Pd-catalyzed cross-coupling are examples of such transformations. In the course of adapting these reactions to protein modification, we learned much about the behavior of these reactions in water, and in some cases entirely new catalysts were developed. Through a combination of these bio-orthogonal transformations from the panel of tag-and-modify reactions, multiple and distinct modifications can be installed on protein surfaces. Multiple modifications are common in natural systems, and synthetic access to these proteins has enabled study of their biological role. Throughout these investigations, much has been learned in chemistry and biology. The demands of selective protein modification have revealed many aspects of reaction mechanisms, which in turn have guided the design of reagents and catalysts that allow their successful deployment in water and in biological milieu. With this ability to modify proteins, it is now possible to interrogate biological systems with precision that was not previously possible.

Trace Amine-Associated Receptor 1 (TAAR1): Molecular and Clinical Insights for the Treatment of Schizophrenia and Related Comorbidities.

Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D2-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairments. For the last few decades, discovery efforts have sought nondopaminergic compounds with the aim to effectively treat the broad symptoms of schizophrenia. In this viewpoint, we provide an overview on trace-amine associated receptor-1 (TAAR1), which presents a clinically validated nondopaminergic target for treating schizophrenia and related disorders, with significantly less overall side-effect burden. TAAR1 agonists may also be specifically beneficial for the substance abuse comorbidity and metabolic syndrome that is often present in patients with schizophrenia.