Halogen Exchange Reaction Research Articles

Reactivity, Pathways, and Iodinated Disinfection Byproduct Formation during Chlorination of Iodotyrosines Derived from Edible Seaweed.

Iodine derived from edible seaweed significantly enhances the formation of iodinated disinfection byproducts (I-DBPs) during household cooking. Reactions of chlorine with monoiodotyrosine (MIT) and diiodotyrosine (DIT) derived from seaweed were investigated. Species-specific second-order rate constants (25 °C) for the reaction of hypochlorous acid with neutral and anionic MIT were calculated to be 23.87 ± 5.01 and 634.65 ± 75.70 M-1 s-1, respectively, while the corresponding rate constants for that with neutral and anionic DIT were determined to be 12.51 ± 19.67 and 199.12 ± 8.64 M-1 s-1, respectively. Increasing temperature facilitated the reaction of chlorine with MIT and DIT. Based on the identification of 59 transformation products/DBPs from iodotyrosines by HPLC/Q-Orbitrap HRMS, three dominant reaction pathways were proposed. Thermodynamic results of computational modeling using density functional theory revealed that halogen exchange reaction follows a stepwise addition-elimination pathway. Among these DBPs, 3,5-diiodo-4-hydroxy-benzaldehyde and 3,5-diiodo-4-hydroxy-benzacetonitrle exhibited high toxic risk. During chlorination of MIT and DIT, iodinated trihalomethanes and haloacetic acids became dominant species at common cooking temperature (80 °C). These results provide insight into the mechanisms of halogen exchange reaction and imply important implications for the toxic risk associated with the exposure of I-DBPs from household cooking with iodine-containing food.

Additive-Free Commercial Alumina Catalyzes the Halogen Exchange Reaction of Long Alkyl Halides in Batch and in Flow Processes

Additive-Free Commercial Alumina Catalyzes the Halogen Exchange Reaction of Long Alkyl Halides in Batch and in Flow Processes

Optical maneuvering of photofunctioning hybrid perovskite for future photonics potential application

Hybrid perovskites, known for their multidimensional opto-electronic properties and capability to generate multi-color emission bands, are highly sought after for light-emitting devices due to their liquid crystalline behavior in the solution phase. This behavior enables easier ion mobility, facilitating ion exchange processes. Exploiting the liquid crystalline properties of perovskites, we applied a halogen exchange reaction in the solution phase using tightly focused laser trapping techniques. Our study demonstrates the successful development of high-luminescent bulk single crystals of methylammonium lead halide alloy MAPb(Br/I)3, which exhibit multi-color emission capabilities, underscoring their potential for optoelectronic applications. We fabricated bulk single crystals of MAPbBr3, measuring 20 × 20 μm2, displaying bright green luminescence. Using a tightly focused trapping laser beam (1064 nm, 1 Watt) with a high numerical aperture (0.9, 60X objective lens), we irradiated a specific area of the green luminescent MAPbBr3 single crystal immersed in a 200 μM methylammonium iodide (MAI) solution for 30 min at room temperature. This treatment induced a red emission band at 605 nm at the irradiated location, while surrounding areas retained the original green luminescence. In a parallel experiment, increasing the iodide concentration to 300 μM caused the emission color of a similar-sized crystal to change uniformly from green to red. Photoluminescence spectroscopy and EDS confirmed the halide exchange from MAPbBr3 to MAPbBr2.3I0.7. This method, influenced by laser parameters such as power, wavelength, and aperture, provides new opportunities for multi-color emission patterning and offers significant insights for advancing optoelectronics.

Rare‐Earth‐Metal Alkyl and Aryl Compounds in Organic Synthesis

AbstractRare‐earth‐metal (Ln) alkyl and aryl compounds feature highly reactive, thermally labile [Ln−C] σ‐bonds which result in rapid and violent decomposition in the presence of air and moisture. Nevertheless, such [Ln−C] moieties display important intermediate species in numerous organic transformations. Reagents containing [Ln−C] bonds are deliberately generated in situ like Imamoto‐type reagents Ln(III)Cl3/RLi (routinely at low temperatures) or “heavy” lanthanide‐Grignard compounds RLnX. Samarium(III)‐alkyl species are supposed intermediates of SmI2‐promoted Barbier‐type carbon–carbon coupling reactions. Alkyl/aryl ligand exchange at Ln(III) centers has been identified as the crucial step of lanthanide–halogen‐exchange reactions. In the meantime, several such mixed alkyl/halogenido complexes, devoid of an ancillary ligand, could be isolated and scrutinized with regard to structure and reactivity. More recently, Ln(III)‐alkylidene complexes could be accessed, structurally authenticated and successfully employed in Tebbe‐like olefination reactions of ketones.

Cobalt(III) Halide Metal-Organic Frameworks Drive Catalytic Halogen Exchange.

The selective halogenation of complex (hetero)aromatic systems is a critical yet challenging transformation that is relevant to medicinal chemistry, agriculture, and biomedical imaging. However, current methods are limited by toxic reagents, expensive homogeneous second- and third-row transition metal catalysts, or poor substrate tolerance. Herein, we demonstrate that porous metal-organic frameworks (MOFs) containing terminal Co(III) halide sites represent a rare and general class of heterogeneous catalysts for the controlled installation of chlorine and fluorine centers into electron-deficient (hetero)aryl bromides using simple metal halide salts. Mechanistic studies support that these halogen exchange (halex) reactions proceed via redox-neutral nucleophilic aromatic substitution (SNAr) at the Co(III) sites. The MOF-based halex catalysts are recyclable, enable green halogenation with minimal waste generation, and facilitate halex in a continuous flow. Our findings represent the first example of SNAr catalysis using MOFs, expanding the lexicon of synthetic transformations enabled by these materials.

Polymeric bis(triphenylphosphine)iminium chloride as a recyclable catalyst.

Metal-free catalysts have garnered considerable interest as an environmental and economical alternative to precious metal catalysts. Bis(triphenylphosphine)iminium chloride (PPNCl) has emerged as a prominent choice due to its air and thermal stability and broad reactivity, especially in applications where a bulky cation is needed. The high phosphorus content and synthetic effort required for catalyst synthesis increase environmental impact; the recyclability of PPNCl in catalytic processes remains largely unexplored. The potential development of a polymer-supported PPNCl catalysts therefore desirable to enable this recyclability. In this work, we synthesise polymeric PPNCl (poly(PPNCl)) for the first time. Poly(PPNCl) demonstrates a comparative catalytic reactivity to its small molecule variant when employed as a catalyst in halogen-exchange reactions and CO2/epoxide coupling. For the latter the effect of catalyst loading, CO2 pressure, reaction time and addition of co-catalyst on conversion and selectivity was investigated. Poly(PPNCl) was easily recovered from the crude product by simple precipitation and its catalytic reactivity was well-maintained over three reaction cycles, providing environmental and economic advantages for sustainable reaction development.

Synthesis and solid state structures of 1,3-dihalo-1,3-bis(dialkylamino)propenium salts and related compounds

1,3-dicholoro-1,3- bis(dialkylamino)propenium salts are prepared by condensing N, N,-dialkylamides with dichloromethylene dimethyliminium chloride (“Viehe's salt”). The products are versatile synthons and can be used to make a variety of ligand types. Here, we report the syntheses of a number of new propenium salts and provide comprehensive characterization data for some that have already been described. Additionally, we have prepared a series of related 1,3-dihalo-1,3- bis(dimethylamino)propenium salts via halogen exchange reactions (F through I). Finally, all of the compounds described, including Viehe's Salt and several hydrolysis products, have been characterized in the solid state using single crystal X-ray diffraction. The symmetrical cations [Me2NC(X)CHC(X)NMe2]+ were found to take one of two general structural forms. The first (X = H or F) is planar, presumably maximizing the delocalization within the backbone of the cation, while the second form is markedly twisted (X = Cl, Br or I). Calculations indicate that the latter develop increasingly positive regions of the electrostatic potential on the halide substituents, allowing cation/anion interactions via halogen bonding to dominate in the extended solids. The results of these studies illustrate the importance of the differing interionic interactions in a homologous series of small organic salts.

Heterometallic complexes of trivalent copper dithiocarbamate with indium and gallium chloride

Heterometallic Cu−In and Cu−Ga complex salts, [Cu(III)(dedtc)2][In(III)Cl4] (1) and [Cu(III)(dedtc)2][Ga(III)Cl4] (2) (dedtc = −S2CNEt2, diethyldithiocarbamate), were synthesized from Cu(II)(dedtc)2, In(III)Cl3, and Ga(III)I3 in dichloromethane and acetone solvents. The trivalent copper complex [Cu(III)(dedtc)2]+ was produced by an oxidation reaction of Cu(II)(dedtc)2 and [M(III)Cl4]– (M = In, Ga) which exhibit a blue-shift of the C–N vibrational mode resulting from the high oxidation state of copper(III) cations. In the Cu−Ga complex salt (2), [Ga(III)Cl4]– was obtained by a halogen exchange reaction between Ga(III)I3 and CH2Cl2. Cu−In and Cu−Ga complex single crystals were grown in benzene and dichloromethane media. Their crystal structures were confirmed that [Cu(III)(dedtc)2]+ units formed distorted octahedral structures with infinite polymeric Cu–S chains surrounded by dimeric [M(III)Cl4]– and benzene. The crystal structures of 1 and 2 included benzene as a guest molecule due to strong noncovalent interactions of metal chloride anions.

On the Dynamic Behavior of Pacman Phosphanes─A Case of Cooperativity and Redox Isomerism.

In solution, the Pacman chlorophosphane (2Cl) shows fast exchange of the endo/exo-orientation of the two P-Cl bonds in the molecule featuring cooperativity. Experimental and quantum mechanical investigations of the inversion on the phosphorus(III) centers reveal a crucial role of chloride ions in the dynamic process. To confirm the results, the homologous Pacman halogen-phosphanes 2X were prepared by halogen exchange reactions (X = F, Br, and I). Besides accelerated dynamic behavior for the heavier analogues, significant differences in the molecular structure are caused by the halogen exchange reactions, including the formation of an endo-endo substituted Pacman fluorophosphane as well as dicationic species by phosphorus halogen bond dissociation. The latter process can be regarded as redox isomerism since two PIII atoms in 2X become PV centers in the dications.

Zeolites catalyze the halogen exchange reaction of alkyl halides

Simple zeolites (NaY, NaX,…) catalyze the halogen switch between two different alkyl halides under either batch or flow reaction conditions. Sodalite cages are proposed to trigger the transformation.

Improvements in Efficiency and Selectivity for C–F Bond Halogen-Exchange Reactions by Using Boron Reagents

AbstractThe use of boron Lewis acids as instigators of bond cleavage offers a number of synthetic possibilities. A unique feature of this class of reagents is the ability to functionalize otherwise inert C–F bonds. We summarize notable developments in C–F bond halogen exchange using Lewis acidic boron reagents and we conclude by featuring our group’s advances in activating CF3 groups by using boron trihalides.1 Introduction2 Boron-Mediated Halogen Exchange3 Mono-Selective C–F Activation4 Conclusions

Resonance and electrostatics making the difference in boron- and aluminum-halide structures and exchange reactivity.

The mechanism of the gas-phase halogen-exchange reaction between boron- and aluminum-halides (i.e., BX3 + BX3 and AlX3 + AlX3, X = F, Cl, or Br) was discovered using density functional theory. The reaction takes place via a two-step mechanism with the intermediacy of a diamond-core structure analogous to diborane. Good agreement was found between the simulated reaction features and experimental observations, which demonstrate slow kinetics and an equilibrium process for boron species and dimer formation in the case of aluminum-halides. This computational and theoretical study also reveals and quantifies the effect of resonance on the thermodynamic stability of the central intermediate and conceptualizes the extreme stability difference (∼50kcal mol-1) between boron and aluminum diamond-core bridge structures. Through an interaction energy decomposition analysis in combination with electronic structure analyses, we revealed that, beyond the resonance stabilization in free boron-halides, superior electrostatics in aluminum-halides results in the different reactivities, i.e., dimer formation for the latter species whereas substituent exchange for the former ones.

Halogen-Exchange Reactions of Iminophosphonamido-Chlorosilylenes with Alkali Halides: Convenient Synthesis of Heavier Halosilylenes.

Halogen-substituted silylenes are an important building block for synthesizing silicon-based low-valent and multiple-bond species. However, the number of reports on heavier halosilylenes that contain bromine and iodine is still limited. Here, we present a convenient synthesis for bromo- and iodosilylenes supported by an iminophosphonamide ligand. The heavier halosilylenes [Ph2P(tBuN)2]SiX (2: X = Br, 3: X = I) were successfully synthesized via the halogen-exchange reaction of chlorosilylene 1 with alkali halides in THF. As a demonstration of the reactivity of 2 and 3, oxidative addition reactions of 2 and 3 with elemental selenium in C6D6 afforded the corresponding bromo- (5) or iodosilylene-selone (6) as colorless crystals. The molecular structures of 2, 3, 5, and 6 were fully characterized by spectroscopic means and single-crystal X-ray diffraction analysis. Furthermore, the effects of the halogen atom on the electronic state of halosilylenes 1-3 and halosilylene-selones 4-6 were investigated using density functional theory (DFT) calculations.

Colorimetric Sensing of Benzoyl Peroxide Based on the Emission Wavelength-Shift of CsPbBr3 Perovskite Nanocrystals

Using the ionic salt characteristics of CsPbBr3 perovskite nanocrystals (CsPbBr3 NCs), the fluorescence wavelength of CsPbBr3−xIx NCs could be changed by the halogen exchange reaction between CsPbBr3 NCs and oleylammonium iodide (OLAM-I). Under the excitation of a 365 nm UV lamp and the increase of OLAM-I concentration, the content of iodine in CsPbBr3−xIx NCs increased, and the fluorescence emission wavelength showed a redshift from 511.6 nm to 593.4 nm, resulting in the fluorescence color change of CsPbBr3 NCs from green to orange-red. Since OLAM-I is a mild reducing agent and easily oxidized by benzoyl peroxide (BPO), a novel colorimetric sensing approach for BPO based on the fluorescence wavelength shift was established in this study. The linear relationship between the different wavelength shifts (Δλ) and the concentration of BPO (CBPO) is found to be in the range of 0 to 120 μmol L−1. The coefficient of alteration (R2) and the detection limit are 0.9933 and 0.13 μmol L−1 BPO, respectively. With this approach, the determination procedure of BPO in flour and noodle samples can be achieved in only a few minutes and exhibit high sensitivity and selectivity.

Halogen exchange in complexes of hexacoordinate tin (LnCH2)2SnX2 and (LnCH2)2SnY2 containing lactamomethyl n-membered C,O-chelate ligands LnCH2 (n=5–7; X, Y = Cl, Br, I)

Halogen exchange reactions between hexacoordinate tin dihalides (LnCH2)2SnX2 and (LnCH2)2SnY2 (LnCH2 = C,O-chelate n-membered lactamomethyl ligand, n = 5–7, X, Y = Cl, Br, I) produce mixed dihalides (LnCH2)2SnXY. Along with the signals of original complexes, NMR 119Sn spectra of solutions containing two different homodihalides show the third signal with a median chemical shift. The results of NMR monitoring studies, conductivity data and quantum-chemical calculations suggest that mixed dihalides readily form in solutions, although these complexes have not been isolated as individual compounds.

Abstract 2863: Preclinical evaluation of astatine-211-conjugated anti-tissue factor antibody

Abstract It has been well-known that tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is overexpressed in various cancers including gastric cancer, pancreatic cancer and malignant gliomas. So far, we produced anti-TF monoclonal antibodies for targeting overexpressed TF in tumor site. Moreover, among them, we found that the clone 1084 possessed deep penetration property leading to more homogenous distribution in tumor than others. Currently, we are focusing on developing clone 1084 antibody armed with alpha emitters for cancer treatment, because alpha-particles are characterized by higher liner energy transfer (LET) and shorter range in tissue than other types of radiation, resulting in efficient deoxyribonucleic acid (DNA) double-strand breaks in cancer cells and minor effects on normal cells adjacent to tumor. In this study, we synthesized astatine-211, one of the most promising alpha-particle emitters, in the 209Bi(α,2n)211At reaction using the RIKEN Azimuthally Varying Field (AVF) cyclotron and labeled humanized clone 1084 with this radionuclide. First, we chemically attached a linker containing organic tin compound to the antibody and then labeled the liker-antibody complex with astatine-211 via a halogen-exchange reaction. Thin-layer chromatography (TLC) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies showed that we successfully labeled the antibody with astatine-211 and purified the radioactive antibody. We evaluated binding activity and in vitro cytocidal effect of the radioactive antibody by flow cytometry and water-soluble tetrazolium salt (WST-8) assay, respectively. The radioactive antibody specifically bound to TF expressed on cell membrane of gastric cancer cells and showed potent cell killing activity depending on TF expression of the cancer cells. Single photon emission computed tomography/computed tomography (SPECT/CT) study revealed that astatine-211 alone selectively accumulated in stomach and thyroid such as radioactive iodine. On the other hand, radioactive antibody showed similar pharmacokinetics to the naked 1084 antibody. Moreover, we confirmed in vivo anti-tumor effects of the radioactive antibody in a TF-overexpressing gastric cancer xenograft model. In conclusion, we successfully created astatine-211-conjugated anti-TF antibody and confirmed its anti-tumor effects. Citation Format: Hiroki Takashima, Yoshikatsu Koga, Kazunobu Onuki, Shino Manabe, Ryo Tsumura, Takahiro Anzai, Nozomi Iwata, Masahiro Yasunaga, Wang Yang, Takuya Yokokita, Yukiko Komori, Daiki Mori, Hiromitsu Haba, Hirofumi Fujii, Yasuhiro Matsumura. Preclinical evaluation of astatine-211-conjugated anti-tissue factor antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2863.

Revealing the Role of Aggregation and Surface Chemistry in the Bi‐phasic Anion Exchange Reactions of Cesium Lead Halide Perovskites

AbstractTuning the emission of cesium lead halide perovskites by the post‐synthetic halogen exchange reactions is one of the easiest methods to obtain the opto‐electronic materials having emission in the entire visible region. Role of aggregation and the surface chemistry on the room temperature bi‐phasic anion exchange reactions of CsPbBr3 nanocrystal is investigated. Aggregation of the nanocrystals resulted in the decrease of surface bromide ions and CsPbBr3 became inactive towards the bi‐phasic anion exchange reactions. On the modification of the surface by enriching with bromide ions, aggregated CsPbBr3 nanocrystals became active towards anion exchange reaction. Surface halide ions have a significant role in the anion exchange reactions and the reaction starts at the surface and diffuses to the inner parts of the crystal as a result of its soft crystal nature. Understanding the role of surface chemistry on the anion exchange reactions, the potential of aggregated CsPbBr3 nanocrystals can be used for the opto‐electronic applications.

Structural and metal-halogen exchange reactivity studies of sodium magnesiate biphenolate complexes.

Bimetallic sodium magnesiates have been employed in metal-halogen exchange for the first time. Utilising the racemic phenoxide ligand 5,5',6,6'-tetramethyl-3,3'-di-tert-butyl-1,1'-biphenyl-2,2'-diol [(rac)-BIPHEN-H2], the dialkyl sodium magnesiates [(rac)-BIPHEN]Na2MgBu2(TMEDA)23 and [(rac)-BIPHEN]Na2MgBu2(PMDETA)24 have been synthesised. Both 3 and 4 can be easily prepared through co-complexation of di-n-butylmagnesium with the sodiated (rac)-BIPHEN precursor which can be prepared in situ in hydrocarbon solvent. Prior to the main investigation, synthesis of the sodiated precursor [BIPHEN]2Na4(THF)41 was explored in order to better understand the formation of sodium magnesiates utilising the dianionic (rac)-BIPHEN ligand as the parent ligand. In addition, a BIPHEN-rich sodium magnesiate [BIPHEN]2Na2Mg(THF)42 was prepared and characterised, and its formation was rationalised. Complex 1 and 4 have also been fully characterised in both solid and solution state. In terms of onward reactivity, 3 and 4 have been tested as potential exchange reagents with aryl and heteroaryl iodides to produce aryl and heteroaryl magnesium phenoxides utilising toluene as a non-polar hydrocarbon solvent. Complex 3 reacted smoothly to give a range of aryl and heteroaryl magnesium phenoxides, whilst 4's reactivity is more sluggish.

Bisaryl Diruthenium(III) Paddlewheel Complexes: Synthesis and Characterization

Aryls represent a class of both σ- and π-donating electron-rich axial ligands that is underexplored in the field of metal–metal multiply bonded paddlewheel species. By a decrease in the steric bulk around the diruthenium axial sites and an increase in the basicity of the bridging ligands, the first examples of bisaryl diruthenium(III) paddlewheel complexes have been isolated. Compounds of the form Ru2(DMBA)4Ar2 (DMBA = N,N′-dimethylbenzamidinate, Ar = C6H4-4-tBu (1), C6H5 (2), C6H3-3,5-(OCH3)2 (3)) were synthesized via a lithium–halogen exchange reaction between Ru2(DMBA)4Cl2 and excess LiAr and characterized using mass spectrometry, electronic absorption spectroscopy, cyclic and differential pulse voltammetry, and 1H NMR spectroscopy. The molecular structures of compounds 1–3 were established using single-crystal X-ray diffraction analysis and their electronic structures (both ground and excited state) analyzed using density functional theory calculations.

Easy Access to 2-Fluoro- and 2-Iodo-2H-azirines via the Halex Reaction

A simple gram-scale method for the preparation of esters and dialkylamides of 2-(fluoro/iodo)-2H-azirine-2-carboxylic acids via the halogen exchange (Halex) reaction of 2-bromo-substituted analogues is reported. The method operates with inexpensive and safe reagents­, Bu4NF and potassium iodide, providing high product yields. Alternatively, 2-fluoro-2H-azirine-2-carboxylates can be prepared from 2-iodo- and 2-chloro-analogues. The latter compounds can be obtained in practically quantitative yield by treating the 2-iodo- and 2-bromo-2H-azirine-2-carboxylic esters with Bu4NCl.