Chlorine Inactivation of Elizabethkingia spp. in Water.

We performed chlorine inactivation experiments for Elizabethkingia anophelis and E. meningoseptica bacterial strains from clinical and environmental sources. Free chlorine concentration × contact time values <0.04 mg·min/L achieved 99.9% inactivation of Elizabethkingia species, indicating chlorine susceptibility. Measures to control biofilm producing pathogens in plumbing are needed to prevent Elizabethkingia bacterial infections.

Biosynthetic mechanism of the yellow pigments in the marine bacterium Pseudoalteromonas sp. strain T1lg65.

The Pseudoalteromonas genus marine bacteria have attracted increasing interest because of their abilities to produce bioactive metabolites. The pigmented Pseudoalteromonas group encodes more secondary metabolite biosynthetic gene clusters (BGCs) than the non-pigmented group. Here, we report a yellow pigmented bacterium Pseudoalteromonas sp. strain T1lg65, which was isolated from a mangrove forest sediment. We showed that the yellow pigments of T1lg65 belong to the group of lipopeptide alterochromides. Further genetic analyses of the alterochromide BGC revealed that the yellow pigments are biosynthesized by aryl-polyene synthases and nonribosomal peptide synthases. Within the gene cluster, altA encodes a tyrosine ammonia acid lyase, which catalyzes synthesis of the precursor 4-hydroxycinnamic acid (4-HCA) from tyrosine in the alterochromide biosynthetic pathway. In addition, altN, encoding a putative flavin-dependent halogenase, was proven to be responsible for the bromination of alterochromides based on gene deletion, molecular docking, and site mutagenesis analyses. In summary, the biosynthetic pathway, precursor synthesis, and bromination mechanism of the lipopeptide alterochromides were studied in-depth. Our results expand the knowledge on biosynthesis of Pseudoalteromonas pigments and could promote the development of active pigments in the future.IMPORTANCEThe marine bacteria Pseudoalteromonas spp. are important biological resources because they are producers of bioactive natural products, including antibiotics, pigments, enzymes, and antimicrobial peptides. One group of the microbial pigments, alterochromides, holds a great value for their novel lipopeptide structures and antimicrobial activities. Previous studies were limited to the structural characterization of alterochromides and genome mining for the alterochromide biosynthesis. This work focused on the biosynthetic mechanism for alterochromide production, especially revealing functions of two key genes within the gene cluster for the alterochromide biosynthesis. On the one hand, our study provides a target for metabolic engineering of the alterochromide biosynthesis; on the other hand, the 4-HCA synthase AltA and brominase AltN show potential in the biocatalyst industry.

Enzymatic Resolution and Decarboxylative Functionalization of α-Sulfinyl Esters.

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides. The method has been applied to the asymmetric synthesis of a potent inhibitor of 15-prostaglandin dehydrogenase.

Efficient Synthesis and Structural Analysis of Chiral 4,4'-Biazulene.

4,4'-Biazulene is a potentially attractive key component of an axially chiral biaryl compound, however, its structure and properties have not been clarified owing to the lack of its efficient synthesis. We report a breakthrough in the reliable synthesis of 4,4'-biazulene, which is achieved by the access to azulen-4-ylboronic acid pinacol ester and 4-iodoazulene as novel key synthetic intermediates for the Suzuki-Miyaura cross-coupling reaction. The X-ray crystallographic analysis of 4,4'-biazulene confirmed its axial chirality. The enantiomers of 4,4'-biazulene were successfully resolved by HPLC on the chiral stationary phase column. The kinetic experiments and DFT calculations indicate that the racemization energy barrier of 4,4'-biazulene is comparable to that of 1,1'-binaphthyl.

200 Years of The Haloform Reaction: Methods and Applications.

Discovered in 1822, the haloform reaction is one of the oldest synthetic organic reactions. The haloform reaction enables the synthesis of carboxylic acids, esters or amides from methyl ketones. The reaction proceeds via exhaustive a-halogenation and then substitution by a nucleophile to liberate a haloform. The methyl group therefore behaves as a masked leaving group. The reaction methodology has undergone several important developments in the last 200 years, transitioning from a diagnostic test of methyl ketones to a synthetically useful tool for accessing complex esters and amides. The success of the general approach has been exhibited through the use of the reaction in the synthesis of many different complex molecules in fields ranging from natural product synthesis, pharmaceuticals, agrochemicals, fragrants and flavouring. The reaction has not been extensively reviewed since 1934. Therefore, herein we provide details of the history and mechanism of the haloform reaction, as well as an overview of the developments in the methodology and a survey of examples, particularly in natural product synthesis, in which the haloform reaction has been used.

Unspecific Peroxygenase (UPO) can be Tuned for Oxygenation or Halogenation Activity by Controlling the Reaction pH.

Unspecific Peroxygenases (UPOs) are increasingly significant enzymes for selective oxygenations as they are stable, highly active and catalyze their reactions at the expense of only hydrogen peroxide as the oxidant. Their structural similarity to chloroperoxidase (CPO) means that UPOs can also catalyze halogenation reactions based upon the generation of hypohalous acids from halide and H2O2. Here we show that the halogenation and oxygenation modes of a UPO can be stimulated at different pH values. Using simple aromatic compounds such as thymol, we show that, at a pH of 3.0 and 6.0, either brominated or oxygenated products respectively are produced. Preparative 100 mg scale transformations of substrates were performed with 60-72 % isolated yields of brominated products obtained. A one-pot bromination-oxygenation cascade reaction on 4-ethylanisole, in which the pH was adjusted from 3.0 to 6.0 at the halfway stage, yielded sequentially brominated and oxygenated products 1-(3-bromo-4-methoxyphenyl)ethyl alcohol and 3-bromo-4-methoxy acetophenone with 82 % combined conversion. These results identify UPOs as an unusual example of a biocatalyst that is tunable for entirely different chemical reactions, dependent upon the reaction conditions.

Fluorination or Not in Small Molecule Solar Cells: Achieving a Higher Efficiency with Halogen-free End Group.

Fluorination is an efficient strategy for improving organic solar cells (OSCs) efficiency, particularly by fluorinating the end group of emerging nonfullerene acceptors. Here, the fluorination effect was investigated by using small molecule donors with fluorine-free (SBz) and fluorinated (SBz-F) end groups, paired with the emerging nonfullerene acceptor Y6. Interestingly and unexpectedly, fluorination of the end group negatively affects OSCs efficiency, with fluorine-free SBz:Y6 OSCs achieving a higher power conversion efficiency (PCE) of 11.05% compared to the fluorine-containing SBz-F:Y6 blends (PCE = 9.61%). Analysis of space-charge limited currents reveals lower and unbalanced hole/electron mobility in SBz-F:Y6 compared to the SBz:Y6 blends. These findings are further supported by charge recombination dynamics and donor-acceptor miscibility analyses.

Halogen and Chalcogen Activation by Nucleophilic Catalysis.

The high utility of halogenated organic compounds has prompted the development of numerous transformations that install the carbon-halogen motif. Halogen functionalities, deemed as "functional and functionalizable" molecules due to their capacity to modulate diverse internal properties, constitute a pivotal strategy in drug discovery and development. Traditional routes to these building blocks have commonly involved multiple steps, harsh reaction conditions, and the use of stoichiometric and/or toxic reagents. With the emergence of solid halogen carriers such as N-halosuccinimides, and halohydantoins as popular sources of halonium ions, the past decade has witnessed enormous growth in the development of new catalytic strategies for halofunctionalization. This review aims to provide a nuanced perspective on nucleophilic activators and their roles in halogen activation. It will highlight critical discoveries in effecting racemic and asymmetric variants of these reactions, driven by the development of new catalysts, activation modes, and improved understanding of chemical reactivity and reaction kinetics.

Telluronium-Catalyzed Halogenation Reactions: Chalcogen-Bond Activation of N-Halosuccinimides and Catalysis.

The ability of triaryltelluronium salts to interact with N-halosuccinimides (NXS) through chalcogen bonding (ChB) in the solid state and in solution is demonstrated herein. Cocrystals of the triaryltelluronium bearing two CF3 electron-withdrawing groups per aryl ring with N-chloro-, N-bromo- and N-iodosuccinimide (respectively NCS, NBS and NIS) were analyzed by X-ray diffraction, evidencing a ChB between tellurium and the carbonyl group of NXS. This ChB was confirmed in solution by NMR spectroscopy, especially by 125Te NMR titration experiment, which allowed the determination of the association constant (Ka) between the telluronium and NBS. The so-obtained Ka value of 17.3±0.6 M-1 indicated a moderate interaction in solution because of the competitive role of the solvent. The strength of the Te⋅⋅⋅O ChB was however sufficient enough to promote the catalytic halofunctionalization of aromatics and of alkenes such as the intra- and intermolecular haloalkoxylation and haloesterification of alkenes.

Synthesis of Novel 4-Acyloxy-2'-Bromo-6'-Chloropodophyllotoxin Derivatives Displaying Significant Insecticidal Activity Against Mythimna Separata.

In order to explore novel natural product-based insecticidal agent, two important intermediates (2 and 3) and 4-acyloxy-2'-bromo-6'-chloropodophyllotoxin derivatives (4 a-f and 5 a-f) were designed and prepared, and their structures were confirmed by 1H-NMR, 13C NMR, HRMS, ESI-MS, optical rotation and melting point (mp). The stereochemical configuration of compound 4 b was unambiguously confirmed by single-crystal X-ray diffraction. Moreover, we evaluated the insecticidal activity of target compounds 4 a-f and 5 a-f against a serious agricultural pest of Mythimna separata by using the leaf-dipping method. Among all tested compounds, compounds 4 d, 5 d and 5 f exhibited stronger insecticidal activity with a final mortality rate exceeding 60 %. Especially compound 5 d exhibited the best insecticidal activity, with a final mortality rate of 74.1 %. It has been proven that introducing bromine or chlorine atoms at the C-2', C-2' and C-6' positions of the E ring of podophyllotoxin can produce more potent compounds. In addition, the configuration of the C-4 position is important for insecticidal activity, and 4ß-configuration is optimal. This will pave the way for further design, structural modification, and development of derivatives of podophyllotoxin as insecticidal agents.

Synthesis of Novel Nitro-Halogenated Aryl-Himachalene Sesquiterpenes from Atlas Cedar Oil Components: Characterization, DFT Studies, and Molecular Docking Analysis against Various Isolated Smooth Muscles.

We report the synthesis of two novel halogenated nitro-arylhimachalene derivatives: 2-bromo-3,5,5,9-tetramethyl-1-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene (bromo-nitro-arylhimachalene) and 2-chloro-3,5,5,9-tetramethyl-1,4-dinitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene (chloro-dinitro-arylhimachalene). These compounds were derived from arylhimachalene, an important sesquiterpene component of Atlas cedar essential oil, via a two-step halogenation and nitration process. Characterization was performed using 1H and 13C NMR spectrometry, complemented by X-ray structural analysis. Quantum chemical calculations employing density functional theory (DFT) with the Becke3-Lee-Yang-parr (B3LYP) functional and a 6-31++G(d,p) basis set were conducted. The optimized geometries of the synthesized compounds were consistent with X-ray structure data. Frontier molecular orbitals and molecular electrostatic potential (MEP) profiles were identified and discussed. DFT reactivity indices provided insights into the compounds' behaviors. Moreover, Hirshfeld surface and 2D fingerprint analyses revealed significant intermolecular interactions within the crystal structures, predominantly H-H and H-O contacts. Molecular docking studies demonstrate strong binding affinities of the synthesized compounds to the active site of protein 7B2W, suggesting potential therapeutic applications against various isolated smooth muscles and neurotransmitters.

Electrochemically Driven Nickel-Catalyzed Halogenation of Unsaturated Halide and Triflate Derivatives.

A robust electrochemically driven nickel-catalyzed halogen exchange of unsaturated halides and triflates (Br to Cl, I to Cl, I to Br, and OTf to Cl) is reported. A combination of NiCl2 ⋅ glyme as the precatalyst, 2,2'-bipyridine as a ligand, NMP as the solvent, and electrochemistry allowed the generation of a nickel species that promotes reductive elimination of the desired product. This paired electrochemical halogenation is compatible with a range of unsaturated halides and triflates, including heterocycles, dihaloarenes, and alkenes with good functional-group tolerance. Joint experimental and theoretical mechanistic investigations highlighted three catalytic events: i) oxidative addition of the aryl halide to a Ni(0) species to deliver a Ni(II) intermediate; ii) halide metathesis at Ni(II); iii) electrochemical oxidation of Ni(II) to Ni(III) to enable the formation of the desired aryl halide upon reductive elimination. This methodology allows the replacement of heavy halogens (I or Br) or polar atoms (O) with the corresponding lighter and more lipophilic Cl group to block undesired reactivity or modify the properties of drug and agrochemical candidates.

Phase-Transfer Catalysis for Electrochemical Chlorination and Nitration of Arenes.

A biphasic anodic oxidation method for aromatic halogenation process was developed, where aqueous metal salts were directly used as halogen source. Ammonium salts serve as both electrolytes and phase transfer catalysis to facilitate anion transport and oxidative transformation. This design allows for chlorination or nitration of multiple types of arenes using NaCl or KNO2.

Direct Benzylic C-H Etherification Enabled by Base-Promoted Halogen Transfer.

We disclose a benzylic C-H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence. The combination of tert-butoxide bases with 2-halothiophene halogen oxidants enables the first general protocol for generating and using benzyl halides through a deprotonative pathway. In contrast to existing radical-based methods for C-H functionalization, this process is guided by C-H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision site-selectivity for polyalkylarenes and use of a double C-H etherification process to controllably oxidize methylarenes to benzaldehydes.

The Influence of Donor/Acceptor Interfaces on Organic Solar Cells Efficiency and Stability Revealed through Theoretical Calculations and Morphology Characterizations.

End-groups halogenation strategies, generally refers to fluorination and chlorination, have been confirmed as simple and efficient methods to regulate the photoelectric performance of non-fullerene acceptors (NFAs), but a controversy over which one is better has existed for a long time. Here, two novel NFAs, C9N3-4F and C9N3-4Cl, featured with different end-groups were successfully synthesized and blended with two renowned donors, D18 and PM6, featured with different electron-withdrawing units. Detailed theoretical calculations and morphology characterizations of the interface structures indicate NFAs based on different end-groups possess different binding energy and miscibility with donors, which shows an obvious influence on phase-separation morphology, charge transport behavior and device performance. After verified by other three pairs of reported NFAs, a universal conclusion obtained as the devices based on D18 with fluorination-end-groups-based NFAs and PM6 with chlorination-end-groups-based NFAs generally show excellent efficiencies, high fill factors and stability. Finally, the devices based on D18: C9N3-4F and PM6: C9N3-4Cl yield outstanding efficiency of 18.53 % and 18.00 %, respectively. Suitably selecting donor and regulating donor/acceptor interface can accurately present the photoelectric conversion ability of a novel NFAs, which points out the way for further molecular design and selection for high-performance and stable organic solar cells.

Precisely Regulating Intermolecular Interactions and Molecular Packing of Nonfused-Ring Electron Acceptors via Halogen Transposition for High-Performance Organic Solar Cells.

The structure of molecular aggregates is crucial for charge transport and photovoltaic performance in organic solar cells (OSCs). Herein, the intermolecular interactions and aggregated structures of nonfused-ring electron acceptors (NFREAs) are precisely regulated through a halogen transposition strategy, resulting in a noteworthy transformation from a 2D-layered structure to a 3D-interconnected packing network. Based on the 3D electron transport pathway, the binary and ternary devices deliver outstanding power conversion efficiencies (PCEs) of 17.46 % and 18.24 %, respectively, marking the highest value for NFREA-based OSCs.

On the Mechanisms of Hypohalous Acid Formation and Electrophilic Halogenation by Non-Native Halogenases.

Enzymatic electrophilic halogenation is a mild tool for functionalization of diverse organic compounds. Only a few groups of native halogenases are capable of catalyzing such a reaction. In this study, we used a mechanism-guided strategy to discover the electrophilic halogenation activity catalyzed by non-native halogenases. As the ability to form a hypohalous acid (HOX) is key for halogenation, flavin-dependent monooxygenases/oxidases capable of forming C4a-hydroperoxyflavin (FlC4a-OOH), such as dehalogenase, hydroxylases, luciferase and pyranose-2-oxidase (P2O), and flavin reductase capable of forming H2O2 were explored for their abilities to generate HOX in situ. Transient kinetic analyses using stopped-flow spectrophotometry/fluorometry and product analysis indicate that FlC4a-OOH in dehalogenases, selected hydroxylases and luciferases, but not in P2O can form HOX; however, the HOX generated from FlC4a-OOH cannot halogenate their substrates. Remarkably, in situ H2O2 generated by P2O can form HOI and also iodinate various compounds. Because not all enzymes capable of forming FlC4a-OOH can react with halides to form HOX, QM/MM calculations, site-directed mutagenesis and structural analysis were carried out to elucidate the mechanism underlying HOX formation and characterize the active site environment. Our findings shed light on identifying new halogenase scaffolds besides the currently known enzymes and have invoked a new mode of chemoenzymatic halogenation.

N-Halogenation by Vanadium-Dependent Haloperoxidases Enables 1,2,4-Oxadiazole Synthesis.

Nitrogen-containing compounds are valuable synthetic intermediates and targets in nearly every chemical industry. While methods for nitrogen-carbon and nitrogen-heteroatom bond formation have primarily relied on nucleophilic nitrogen atom reactivity, molecules containing nitrogen-halogen bonds allow for electrophilic or radical reactivity modes at the nitrogen center. Despite the growing synthetic utility of nitrogen-halogen bond-containing compounds, selective catalytic strategies for their synthesis are largely underexplored. We recently discovered that the vanadium-dependent haloperoxidase (VHPO) class of enzymes are a suitable biocatalyst platform for nitrogen-halogen bond formation. Herein, we show that VHPOs perform selective halogenation of a range of substituted benzamidine hydrochlorides to produce the corresponding N'-halobenzimidamides. This biocatalytic platform is applied to the synthesis of 1,2,4-oxadiazoles from the corresponding N-acylbenzamidines in high yield and with excellent chemoselectivity. Finally, the synthetic applicability of this biotechnology is demonstrated in an extension to nitrogen-nitrogen bond formation and the chemoenzymatic synthesis of the Duchenne muscular dystrophy drug, ataluren.

Site-Selective Distal C(sp3)-H Bromination of Aliphatic Amines as a Gateway for Forging Nitrogen-Containing sp3 Architectures.

Herein, we disclose a new strategy that rapidly and reliably incorporates bromine atoms at distal, secondary C(sp3)-H sites in aliphatic amines with an excellent and predictable site-selectivity pattern. The resulting halogenated building blocks serve as versatile linchpins to enable a series of carbon-carbon and carbon-heteroatom bond-formations at remote C(sp3) sites, thus offering a new modular and unified platform that expediates the access to advanced sp3 architectures possessing valuable nitrogen-containing saturated heterocycles of interest in medicinal chemistry settings.

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and ß-substituted 5-hexenoic acids.

Enantioselective halolactonizations of sterically less hindered alkenoic acid substrates without substituents on the carbon-carbon double bond have remained a formidable challenge. To address this limitation, we report herein the asymmetric bromolactonization of 5-hexenoic acid derivatives catalyzed by a BINOL-derived chiral bifunctional sulfide.