Biochemistry of Catabolic Reductive Dehalogenation.

A wide range of phylogenetically diverse microorganisms couple the reductive dehalogenation of organohalides to energy conservation. Key enzymes of such anaerobic catabolic pathways are corrinoid and Fe-S cluster-containing, membrane-associated reductive dehalogenases. These enzymes catalyze the reductive elimination of a halide and constitute the terminal reductases of a short electron transfer chain. Enzymatic and physiological studies revealed the existence of quinone-dependent and quinone-independent reductive dehalogenases that are distinguishable at the amino acid sequence level, implying different modes of energy conservation in the respective microorganisms. In this review, we summarize current knowledge about catabolic reductive dehalogenases and the electron transfer chain they are part of. We review reaction mechanisms and the role of the corrinoid and Fe-S cluster cofactors and discuss physiological implications.

Catalysis of an SN2 pathway by geometric preorganization.

Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor catalyst accelerates the SN2 step of an enantioselective Michaelis-Arbuzov reaction by recapitulating the geometric preorganization principle used by enzymes. Mechanistic and computational investigations show that the hydrogen-bond donor diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.

Natural short-lived halogens exert an indirect cooling effect on climate.

Observational evidence shows the ubiquitous presence of ocean-emitted short-lived halogens in the global atmosphere1-3. Natural emissions of these chemical compounds have been anthropogenically amplified since pre-industrial times4-6, while, in addition, anthropogenic short-lived halocarbons are currently being emitted to the atmosphere7,8. Despite their widespread distribution in the atmosphere, the combined impact of these species on Earth's radiative balance remains unknown. Here we show that short-lived halogens exert a substantial indirect cooling effect at present (-0.13 ± 0.03 watts per square metre) that arises from halogen-mediated radiative perturbations of ozone (-0.24 ± 0.02 watts per square metre), compensated by those from methane (+0.09 ± 0.01 watts per square metre), aerosols (+0.03 ± 0.01 watts per square metre) and stratospheric water vapour (+0.011 ± 0.001 watts per square metre). Importantly, this substantial cooling effect has increased since 1750 by -0.05 ± 0.03 watts per square metre (61 per cent), driven by the anthropogenic amplification of natural halogen emissions, and is projected to change further (18-31 per cent by 2100) depending on climate warming projections and socioeconomic development. We conclude that the indirect radiative effect due to short-lived halogens should now be incorporated into climate models to provide a more realistic natural baseline of Earth's climate system.

Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens.

Antimicrobial resistance presents us with a potential global crisis as it undermines the abilities of conventional antibiotics to combat pathogenic microbes. The history of antimicrobial agents is replete with examples of scaffolds containing halogens. In this review, we discuss the impacts of halogen atoms in various antibiotic types and antimicrobial scaffolds and their modes of action, structure-activity relationships, and the contributions of halogen atoms in antimicrobial activity and drug resistance. Other halogenated molecules, including carbohydrates, peptides, lipids, and polymeric complexes, are also reviewed, and the effects of halogenated scaffolds on pharmacokinetics, pharmacodynamics, and factors affecting antimicrobial and antivirulence activities are presented. Furthermore, the potential of halogenation to circumvent antimicrobial resistance and rejuvenate impotent antibiotics is addressed. This review provides an overview of the significance of halogenation, the abilities of halogens to interact in biomolecular settings and enhance pharmacological properties, and their potential therapeutic usages in preventing a postantibiotic era. SIGNIFICANCE STATEMENT: Antimicrobial resistance and the increasing impotence of antibiotics are critical threats to global health. The roles and importance of halogen atoms in antimicrobial drug scaffolds have been established, but comparatively little is known of their pharmacological impacts on drug resistance and antivirulence activities. This review is the first to extensively evaluate the roles of halogen atoms in various antibiotic classes and pharmacological scaffolds and to provide an overview of their ability to overcome antimicrobial resistance.

Emerging Chalcohalide Materials for Energy Applications.

Semiconductors with multiple anions currently provide a new materials platform from which improved functionality emerges, posing new challenges and opportunities in material science. This review has endeavored to emphasize the versatility of the emerging family of semiconductors consisting of mixed chalcogen and halogen anions, known as "chalcohalides". As they are multifunctional, these materials are of general interest to the wider research community, ranging from theoretical/computational scientists to experimental materials scientists. This review provides a comprehensive overview of the development of emerging Bi- and Sb-based as well as a new Cu, Sn, Pb, Ag, and hybrid organic-inorganic perovskite-based chalcohalides. We first highlight the high-throughput computational techniques to design and develop these chalcohalide materials. We then proceed to discuss their optoelectronic properties, band structures, stability, and structural chemistry employing theoretical and experimental underpinning toward high-performance devices. Next, we present an overview of recent advancements in the synthesis and their wide range of applications in energy conversion and storage devices. Finally, we conclude the review by outlining the impediments and important aspects in this field as well as offering perspectives on future research directions to further promote the development of chalcohalide materials in practical applications in the future.

Structure-activity relationship of 2,4-D correlates auxinic activity with the induction of somatic embryogenesis in Arabidopsis thaliana.

2,4-dichlorophenoxyacetic acid (2,4-D) is a synthetic analogue of the plant hormone auxin that is commonly used in many in vitro plant regeneration systems, such as somatic embryogenesis (SE). Its effectiveness in inducing SE, compared to the natural auxin indole-3-acetic acid (IAA), has been attributed to the stress triggered by this compound rather than its auxinic activity. However, this hypothesis has never been thoroughly tested. Here we used a library of forty 2,4-D analogues to test the structure-activity relationship with respect to the capacity to induce SE and auxinic activity in Arabidopsis thaliana. Four analogues induced SE as effectively as 2,4-D and 13 analogues induced SE but were less effective. Based on root growth inhibition and auxin response reporter expression, the 2,4-D analogues were classified into different groups, ranging from very active to not active auxin analogues. A halogen at the 4-position of the aromatic ring was important for auxinic activity, whereas a halogen at the 3-position resulted in reduced activity. Moreover, a small substitution at the carboxylate chain was tolerated, as was extending the carboxylate chain with an even number of carbons. The auxinic activity of most 2,4-D analogues was consistent with their simulated TIR1-Aux/IAA coreceptor binding characteristics. A strong correlation was observed between SE induction efficiency and auxinic activity, which is in line with our observation that 2,4-D-induced SE and stress both require TIR1/AFB auxin co-receptor function. Our data indicate that the stress-related effects triggered by 2,4-D and considered important for SE induction are downstream of auxin signalling.

Detection of Bromochloro Alkanes in Indoor Dust Using a Novel CP-Seeker Data Integration Tool.

Bromochloro alkanes (BCAs) have been manufactured for use as flame retardants for decades, and preliminary environmental risk screening suggests they are likely to behave similarly to polychlorinated alkanes (PCAs), subclasses of which are restricted as Stockholm Convention Persistent Organic Pollutants (POPs). BCAs have rarely been studied in the environment, although some evidence suggests they may migrate from treated-consumer materials into indoor dust, resulting in human exposure via inadvertent ingestion. In this study, BCA-C14 mixture standards were synthesized and used to validate an analytical method. This method relies on chloride-enhanced liquid chromatography-electrospray ionization-Orbitrap-high resolution mass spectrometry (LC-ESI-Orbitrap-HRMS) and a novel CP-Seeker integration software package for homologue detection and integration. Dust sample preparation via ultrasonic extraction, acidified silica cleanup, and fractionation on neutral silica cartridges was found to be suitable for BCAs, with absolute recovery of individual homologues averaging 66 to 78% and coefficients of variation ≤10% in replicated spiking experiments (n = 3). In addition, a total of 59 indoor dust samples from six countries, including Australia (n = 10), Belgium (n = 10), Colombia (n = 10), Japan (n = 10), Thailand (n = 10), and the United States of America (n = 9), were analyzed for BCAs. BCAs were detected in seven samples from the U.S.A., with carbon chain lengths of C8, C10, C12, C14, C16, C18, C24 to C28, C30 and C31 observed overall, though not detected in samples from any other countries. Bromine numbers of detected homologues in the indoor dust samples ranged Br1-4 as well as Br7, while chlorine numbers ranged Cl2-11. BCA-C18 was the most frequently detected, observed in each of the U.S.A. samples, while the most prevalent degrees of halogenation were homologues of Br2 and Cl4-5. Broad estimations of BCA concentrations in the dust samples indicated that levels may approach those of other flame retardants in at least some instances. These findings suggest that development of quantification strategies and further investigation of environmental occurrence and health implications are needed.

Structure-based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL-5R/IL-5 interaction by gluing halogen bonds at their complex interface.

Human interleukin-5 (IL-5) cytokine mediates the development of eosinophils and is involved in a variety of immune inflammatory responses that play a major role in the pathogenesis of childhood asthma, leukemia, and other pediatric allergic diseases. The immunomodulatory cytokine functions by binding to its cognate cell surface receptor IL-5R in a sheet-by-sheet manner, which can be conformationally mimicked and competitively disrupted by a double-stranded cyclic AF18748 peptide. In this study, we systematically examined the co-crystallized complex structure of human IL-5R with AF18748 peptide and rationally designed a halogen bond to glue at the protein-peptide complex interface by substituting the indole moiety of AF18748 Trp13 residue with a halogen atom (X = F, Cl, Br, or I). High-level theoretical calculations imparted presence of the halogen bond between the oxygen atom (O) of IL-5R Glu58 backbone and the halogen atom (X) of AF18748 Trp13 side chain. Experimental assays confirmed that the halogen bond can promote peptide binding moderately or considerably. More importantly, the halogen bond not only enhances peptide affinity to IL-5R, but also improves peptide selectivity for its cognate IL-5R over other noncognate IL-R proteins. As might be expected, the affinity and selectivity conferred by halogen bond increase consistently in the order: H < F < Cl < Br < I. Structural modeling revealed that the halogen bond plus its vicinal π-cation-π stacking co-define a ringed noncovalent system at the complex interface, which involves a synergistic effect to effectively improve the peptide binding potency and recognition specificity.

Reaction pathway engineering converts a radical hydroxylase into a halogenase.

FeII/α-ketoglutarate (FeII/αKG)-dependent enzymes offer a promising biocatalytic platform for halogenation chemistry owing to their ability to functionalize unactivated C-H bonds. However, relatively few radical halogenases have been identified to date, limiting their synthetic utility. Here, we report a strategy to expand the palette of enzymatic halogenation by engineering a reaction pathway rather than substrate selectivity. This approach could allow us to tap the broader class of FeII/αKG-dependent hydroxylases as catalysts by their conversion to halogenases. Toward this goal, we discovered active halogenases from a DNA shuffle library generated from a halogenase-hydroxylase pair using a high-throughput in vivo fluorescent screen coupled to an alkyne-producing biosynthetic pathway. Insights from sequencing halogenation-active variants along with the crystal structure of the hydroxylase enabled engineering of a hydroxylase to perform halogenation with comparable activity and higher selectivity than the wild-type halogenase, showcasing the potential of harnessing hydroxylases for biocatalytic halogenation.

Diphenylene Iodonium as a Prominent Halogen Bond Donor: The Case of Human Monoamine Oxidase B.

Herein we have investigated the formation and interplay of several noncovalent interactions (NCIs) involved in the inhibition of human monoamine oxidase B (MAO B). Concretely, an inspection of the Protein Data Bank (PDB) revealed the formation of a halogen bond (HlgB) between a diphenylene iodonium (DPI) inhibitor and a water molecule present in the active site, in addition to a noncovalent network of interactions (e. g. lone pair-π, hydrogen bonding, OH-π, CH-π and π-stacking interactions) with surrounding protein residues. Several theoretical models were built to understand the strength and directionality features of the HlgB in addition to the interplay with other NCIs present in the active site of the enzyme. Besides, a computational study was carried out using DPI as HlgB donor and several electron rich molecules (CO, H2O, CH2O, HCN, pyridine, OCN-, SCN-, Cl- and Br-) as HlgB acceptors. The results were analyzed using several state-of-the-art computational tools. We expect that our results will be useful for those scientists working in the fields of rational drug design, chemical biology as well as supramolecular chemistry.

Molecular Interaction Fields Describing Halogen Bond Formable Areas on Protein Surfaces.

Molecular interaction fields (MIFs) are three-dimensional interaction maps that describe the intermolecular interactions expected to be formed around target molecules. In this paper, a method for the fast computation of MIFs using the approximation functions of quantum mechanics-level MIFs of small model molecules is proposed. MIF functions of N-methylacetamide with chlorobenzene, bromobenzene, and iodobenzene probes were precisely approximated and used to calculate the MIFs on protein surfaces. This method appropriately reproduced halogen-bond-formable areas around the ligand-binding sites of proteins, where halogen bond formation was suggested in a previous study.

Applications of Halogen-Atom Transfer (XAT) for the Generation of Carbon Radicals in Synthetic Photochemistry and Photocatalysis.

The halogen-atom transfer (XAT) is one of the most important and applied processes for the generation of carbon radicals in synthetic chemistry. In this review, we summarize and highlight the most important aspects associated with XAT and the impact it has had on photochemistry and photocatalysis. The organization of the material starts with the analysis of the most important mechanistic aspects and then follows a subdivision based on the nature of the reagents used in the halogen abstraction. This review aims to provide a general overview of the fundamental concepts and main agents involved in XAT processes with the objective of offering a tool to understand and facilitate the development of new synthetic radical strategies.

Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups.

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

Synthesis and Glycosidation of Anomeric Halides: Evolution from Early Studies to Modern Methods of the 21st Century.

Advances in synthetic carbohydrate chemistry have dramatically improved access to common glycans. However, many novel methods still fail to adequately address challenges associated with chemical glycosylation and glycan synthesis. Since a challenge of glycosylation has remained, scientists have been frequently returning to the traditional glycosyl donors. This review is dedicated to glycosyl halides that have played crucial roles in shaping the field of glycosciences and continue to pave the way toward our understanding of chemical glycosylation.

Pioneering Piezoelectric-Driven Atomic Hydrogen for Efficient Dehalogenation of Halogenated Organic Pollutants.

The electrocatalytic hydrodehalogenation (EHDH) process mediated by atomic hydrogen (H*) is recognized as an efficient method for degrading halogenated organic pollutants (HOPs). However, a significant challenge is the excessive energy consumption resulting from the recombination of H* to H2 production in the EHDH process. In this study, a promising strategy was proposed to generate piezo-induced atomic H*, without external energy input or chemical consumption, for the degradation and dehalogenation of HOPs. Specifically, sub-5 nm Ni nanoparticles were subtly dotted on an N-doped carbon layer coating on BaTiO3 cube, and the resulted hybrid nanocomposite (Ni-NC@BTO) can effectively break C-X (X = Cl and F) bonds under ultrasonic vibration or mechanical stirring, demonstrating high piezoelectric driven dehalogenation efficiencies toward various HOPs. Mechanistic studies revealed that the dotted Ni nanoparticles can efficiently capture H* to form Ni-H* (Habs) and drive the dehalogenation process to lower the toxicity of intermediates. COMSOL simulations confirmed a "chimney effect" on the interface of Ni nanoparticle, which facilitated the accumulation of H+ and enhanced electron transfer for H* formation by improving the surface charge of the piezocatalyst and strengthening the interfacial electric field. Our work introduces an environmentally friendly dehalogenation method for HOPs using the piezoelectric process independent of the external energy input and chemical consumption.

Recent Advancements in Pyrolysis of Halogen-Containing Plastics for Resource Recovery and Halogen Upcycling: A State-of-the-Art Review.

Plastic waste has emerged as a serious issue due to its impact on environmental degradation and resource scarcity. Plastic recycling, especially of halogen-containing plastics, presents challenges due to potential secondary pollution and lower-value implementations. Chemical recycling via pyrolysis is the most versatile and robust approach for combating plastic waste. In this Review, we present recent advancements in halogen-plastic pyrolysis for resource utilization and the potential pathways from "reducing to recycling to upcycling" halogens. We emphasize the advanced management of halogen-plastics through copyrolysis with solid wastes (waste polymers, biomass, coal, etc.), which is an efficient method for dealing with mixed wastes to obtain high-value products while reducing undesirable substances. Innovations in catalyst design and reaction configurations for catalytic pyrolysis are comprehensively evaluated. In particular, a tandem catalysis system is a promising route for halogen removal and selective conversion of targeted products. Furthermore, we propose novel insights regarding the utilization and upcycling of halogens from halogen-plastics. This includes the preparation of halogen-based sorbents for elemental mercury removal, the halogenation-vaporization process for metal recovery, and the development of halogen-doped functional materials for new materials and energy applications. The reutilization of halogens facilitates the upcycling of halogen-plastics, but many efforts are needed for mutually beneficial outcomes. Overall, future investigations in the development of copyrolysis and catalyst-driven technologies for upcycling halogen-plastics are highlighted.

Effects of Halides on Organic Compound Degradation during Plasma Treatment of Brines.

Plasma has been proposed as an alternative strategy to treat organic contaminants in brines. Chemical degradation in these systems is expected to be partially driven by halogen oxidants, which have been detected in halide-containing solutions exposed to plasma. In this study, we characterized specific mechanisms involving the formation and reactions of halogen oxidants during plasma treatment. We first demonstrated that addition of halides accelerated the degradation of a probe compound known to react quickly with halogen oxidants (i.e., para-hydroxybenzoate) but did not affect the degradation of a less reactive probe compound (i.e., benzoate). This effect was attributed to the degradation of para-hydroxybenzoate by hypohalous acids, which were produced via a mechanism involving halogen radicals as intermediates. We applied this mechanistic insight to investigate the impact of constituents in brines on reactions driven by halogen oxidants during plasma treatment. Bromide, which is expected to occur alongside chloride in brines, was required to enable halogen oxidant formation, consistent with the generation of halogen radicals from the oxidation of halides by hydroxyl radical. Other constituents typically present in brines (i.e., carbonates, organic matter) slowed the degradation of organic compounds, consistent with their ability to scavenge species involved during plasma treatment.

A Heteroatom-Containing Functional Poly(Silylenevinylene): Synthesis, Anion Binding, and Sensing of Anion Extraction Processes.

Catalytic hydrosilylation is one of the important synthetic approaches to prepare functional organosilicon polymers. Herein, a functional silicon copolymer is constructed by polyhydrosilylation reaction between a novel 3,7-bis(dimethyl silane)-10-(2-ethylhexyl)-10H-phenothiazine monomer and a neutral tetrapyrrolic macrocycle, namely, 5,5,10,15,15,20-hexamethyl-10α, 20α-bis(4-[ethynylphenyl]) calix[4]pyrrole. The as-constructed copolymer (Mn  = 9609, PDI = 2.2) is investigated as an extractant for organic anions as their tetrabutylammonium salts under interfacial aqueous-organic (water-chloroform) conditions. In this context, a distinctive naked-eye colorimetric as well as fluorescence detection method is developed based on anion-directed hydrogen-bonding interactions. This kind of color/fluorescence monitoring serves as a handy tool for rapid screening of anion extraction processes. The copolymer exhibits high selectivity toward extraction of chloride anion. This study augments the field of polycarbosilanes, poly(silylenevinylene)s in particular, allowing access to a new application window that can be further advanced with good grace in near future.

Reactive Halogen Species: Role in Living Systems and Current Research Approaches.

Reactive halogen species (RHS) are highly reactive compounds that are normally required for regulation of immune response, inflammatory reactions, enzyme function, etc. At the same time, hyperproduction of highly reactive compounds leads to the development of various socially significant diseases - asthma, pulmonary hypertension, oncological and neurodegenerative diseases, retinopathy, and many others. The main sources of (pseudo)hypohalous acids are enzymes from the family of heme peroxidases - myeloperoxidase, lactoperoxidase, eosinophil peroxidase, and thyroid peroxidase. Main targets of these compounds are proteins and peptides, primarily methionine and cysteine residues. Due to the short lifetime, detection of RHS can be difficult. The most common approach is detection of myeloperoxidase, which is thought to reflect the amount of RHS produced, but these methods are indirect, and the results are often contradictory. The most promising approaches seem to be those that provide direct registration of highly reactive compounds themselves or products of their interaction with components of living cells, such as fluorescent dyes. However, even such methods have a number of limitations and can often be applied mainly for in vitro studies with cell culture. Detection of reactive halogen species in living organisms in real time is a particularly acute issue. The present review is devoted to RHS, their characteristics, chemical properties, peculiarities of interaction with components of living cells, and methods of their detection in living systems. Special attention is paid to the genetically encoded tools, which have been introduced recently and allow avoiding a number of difficulties when working with living systems.