Molecular Bromine Research Articles

Use of Bromine and Bromo-Organic Compounds in Organic Synthesis

Bromination is one of the most important transformations in organic synthesis and can be carried out using bromine and many other bromo compounds. Use of molecular bromine in organic synthesis is well-known. However, due to the hazardous nature of bromine, enormous growth has been witnessed in the past several decades for the development of solid bromine carriers. This review outlines the use of bromine and different bromo-organic compounds in organic synthesis. The applications of bromine, a total of 107 bromo-organic compounds, 11 other brominating agents, and a few natural bromine sources were incorporated. The scope of these reagents for various organic transformations such as bromination, cohalogenation, oxidation, cyclization, ring-opening reactions, substitution, rearrangement, hydrolysis, catalysis, etc. has been described briefly to highlight important aspects of the bromo-organic compounds in organic synthesis.

ChemInform Abstract: Aerobic Oxidative Bromination of Arenes Using an Ionic Liquid as Both the Catalyst and the Solvent.

Abstract A method for the bromination of alkoxy-substituted benzenes and naphthalenes was developed by using the residual oxygen in the reaction tube as the oxidant, and [Bmim]NO 3 (1-butyl-3-methylimidazolium nitrate) ionic liquid as both the catalyst and the solvent. No other reagent apart from the ionic liquid and molecular bromine was used in the reactions, and basically all the bromine atoms in the bromine source were transferred to the bromination products, showing that the presented protocol is highly atom economic and practical.

Trapping molecular bromine: a one-dimensional bromobismuthate complex with Br2 as a linker.

The reaction between solid (NMP)n{[BiBr4]}n (1) (NMP = N-methylpyridinium) and Br2, generated in situ in HBr solution, results in the formation of (NMP)3[Bi2Br9]·Br2 (2). In the structure of 2, dibromine molecules connect discrete binuclear [Bi2Br9](3-) anions into an extended network. Complex 2 is thermally stable (up to 150 °C).

Factors influencing the formation of polybromide monoanions in solutions of ionic liquid bromide salts.

Six different bromide salts - tetraethylammonium bromide ([N2,2,2,2]Br, Br), 1-ethyl-1-methylpiperidinium bromide ([C2MPip]Br, Br), 1-ethyl-1-methylpyrrolidinium bromide ([C2MPyrr]Br, Br), 1-ethyl-3-methylimidazolium bromide ([C2MIm]Br, Br), 1-ethylpyridinium bromide ([C2Py]Br, Br), and 1-(2-hydroxyethyl)pyridinium bromide ([C2OHPy]Br, Br) - were studied in regards to their capacity to form polybromide monoanion products on addition of molecular bromine in acetonitrile solutions. Using complementary spectroscopic and computational methods for the examination of tribromide and pentabromide anion formation, key factors influencing polybromide sequestration were identified. Here, we present criteria for the targeted synthesis of highly efficient bromine sequestration agents.

Primary alkanols: oxidative homocondensation in water and cross-condensation in methanol

Water was used as a reaction medium and a reagent in oxidation of primary alkanols to dimeric esters and alkanoic acids using either molecular bromine or a hydrogen peroxide—hydrobromic acid mixture as the oxidants. The similar reaction in methanol produced methyl alkanoates.

Aerobic oxidative bromination of arenes using an ionic liquid as both the catalyst and the solvent

A method for the bromination of alkoxy-substituted benzenes and naphthalenes was developed by using the residual oxygen in the reaction tube as the oxidant, and [Bmim]NO3 (1-butyl-3-methylimidazolium nitrate) ionic liquid as both the catalyst and the solvent. No other reagent apart from the ionic liquid and molecular bromine was used in the reactions, and basically all the bromine atoms in the bromine source were transferred to the bromination products, showing that the presented protocol is highly atom economic and practical.

Bromination of 2,7′-bi-indolyls and quinazolin-7-ones

Efficient regioselective procedures for bromination of 2,7′-bi-indolyls and quinazolin-7-ones using molecular bromine and N-bromosuccinimide were developed to afford a wide range of novel mono-, di-, tri- and tetrabrominated derivatives with various substitution patterns. Protection of the nitrogen atoms in the 2,7′-bi-indolyl scaffold by acetyl, benzenesulfonyl and carbonyl groups was investigated. Stability of 2,7′-bi-indolyls in the presence of strong bases was explored to discover formation of imines followed by the unusual ring opening reaction. Single crystal X-ray crystallography and NMR spectroscopy were employed in order to assign structural isomers of dibrominated quinazolin-7-ones. A new method for the synthesis of macrocyclic tetra-indolyls via acid-catalyzed coupling of monobromo-2,7′-bi-indolyls is reported and a possible mechanism of the reaction presented.

Production mechanism of active species on the oxidative bromination following perhydrolase activity

Hypobromous acid and molecular bromine have been described as the active species involved in the oxidative bromination using perhydrolase, which catalyzes the reaction from acetic acid and hydrogen peroxide to peracetic acid (AcOOH). However, the brominating activity of them in a chemical model system was lower than that of the active species produced by the spontaneous reaction between AcOOH and Br−. Consequently, acetyl hypobromite (AcOBr) was suggested as new active species on the bromination by detection of the decarboxylation in the reaction between AcOOH and Br− and the strong brominating power with some tolerance against H2O2. Its production mechanism was explained as the ionic reaction involving the protonated intermediate of AcOOH by kinetic analysis. Copyright © 2015 John Wiley & Sons, Ltd.

Влияние бромирования метилового эфира 1-аллил-4-гидрокси-2,2-диоксо-1<i>H</i>-2λ<sup>6</sup>,1-бензотиазин-3-карбоновой кислоты на фармакологические свойства

С помощью рентгеноструктурного анализа установлено, что, в отличие от близких по строению алкил-1-аллил-4-гидрокси-2-оксо-1,2-дигидрохинолин-3-карбоксилатов, взаимодействие метилового эфира 1-аллил-4-гидрокси-2,2-диоксо-1H-2λ6,1-бензотиазин-3-карбоновой кислоты с молекулярным бромом в среде ледяной уксусной кислоты представляет собой не гетероциклизацию, а классическое присоединение брома к ненасыщенной аллильной связи. Фармакологические испытания показали, что в случае сложных эфиров удаление из 1-N-алкильного фрагмента двойной связи сопровождается спадом анальгетической активности.

Mechanistic Details of Pd(II)-Catalyzed C-H Iodination with Molecular I2: Oxidative Addition vs Electrophilic Cleavage.

Transition metal-catalyzed C-H bond halogenation is an important alternative to the highly utilized directed-lithiation methods and increases the accessibility of the synthetically valuable aryl halide compounds. However, this approach often requires impractical reagents, such as IOAc, or strong co-oxidants. Therefore, the development of methodology utilizing inexpensive oxidants and catalyst containing earth-abundant transition metals under mild experimental conditions would represent a significant advance in the field. Success in this endeavor requires a full understanding of the mechanisms and reactivity governing principles of this process. Here, we report intimate mechanistic details of the Pd(II)-catalyzed C-H iodination with molecular I2 as the sole oxidant. Namely, we elucidate the impact of the: (a) Pd-directing group (DG) interaction, (b) nature of oxidant, and (c) nature of the functionalized C-H bond [C(sp(2))-H vs C(sp(3))-H] on the Pd(II)/Pd(IV) redox and Pd(II)/Pd(II) redox-neutral mechanisms of this reaction. We find that both monomeric and dimeric Pd(II) species may act as an active catalyst during the reaction, which preferentially proceeds via the Pd(II)/Pd(II) redox-neutral electrophilic cleavage (EC) pathway for all studied substrates with a functionalized C(sp(2))-H bond. In general, a strong Pd-DG interaction increases the EC iodination barrier and reduces the I-I oxidative addition (OA) barrier. However, the increase in Pd-DG interaction alone is not enough to make the mechanistic switch from EC to OA: This occurs only upon changing to substrates with a functionalized C(sp(3))-H bond. We also investigated the impact of the nature of the electrophile on the C(sp(2))-H bond halogenation. We predicted molecular bromine (Br2) to be more effective electrophile for the C(sp(2))-H halogenation than I2. Subsequent experiments on the stoichiometric C(sp(2))-H bromination by Pd(OAc)2 and Br2 confirmed this prediction.The findings of this study advance our ability to design more efficient reactions with inexpensive oxidants under mild experimental conditions.

Bromination of highly unsaturated trifluoromethanesulfonamide derivatives

The bromination of trifluoro-N-(prop-2-yn-1-yl)methanesulfonamide with molecular bromine gives a mixture of Z- and E-isomeric N-(2,3-dibromoprop-2-en-1-yl)trifluoromethanesulfonamides, regardless of the reaction conditions. Bromine adds to both triple bonds of trifluoro-N,N-bis(prop-2-yn-1-yl)methanesulfonamide, yielding a mixture of N-(2,3-dibromprop-2-en-1-yl)trifluoro-N-(prop-2-yn-1-yl)methanesulfonamide, N,N-bis(2,3-dibromoprop-2-en-1-yl)trifluoromethanesulfonamide, and trifluoro-N,N-bis(2,2,3,3-tetrabromopropyl) methanesulfonamide. Diacetylenic trifluoromethanesulfonamide derivative, N,N′-hexa-2,4-diyne-1,6-diylbis( trifluoromethanesulfonamide), reacts with bromine to afford N,N′-[(2E,4E)-2,3,4,5-tetrabromohexa-2,4-diene-1,6-diyl]bis(trifluoromethanesulfonamide) and isomeric N-(2,3-dibromoprop-2-en-1-yl)trifluoromethanesulfonamides resulting from reductive cleavage of the central C–C bond in the former.

Synthesis, Characterization, and Application of Poly(N,N′-dibromo-N-ethylnaphthyl-2,7-disulfonamide) as an Efficient Reagent for the Synthesis of 2-Arylbenzimidazole and 2-Aryl-1-arylmethyl-1H-1,3-benzimidazole Derivatives

The condensation of O-phenylenediamine (OPD) with aryl aldehydes is carried out in acetonitrile using poly(N,N′-dibromo-N-ethylnaphthyl-2,7-disulfonamide) (PBNS) as a novel and heterogeneous catalyst. PBNS has some potential advantages which include ease of separation from the reaction mixture by simple filtration, easy preparation, recoverablility, convenience, and stability under normal condition and also is not dangerous as molecular bromine.

Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives

In this study, series of novel bromophenol derivatives were synthesized and investigated for their antioxidant and AChE inhibition properties. Novel brominated diarylmethanones were obtained from the acylation reactions of benzoic acids with substituted benzenes. One of the bromodiarylmethanone was synthesized from the bromination of diarylmethanone with molecular bromine. All diarylmethanones were converted into their bromophenol derivatives with BBr3. The antioxidant activities of all synthesized compounds were elucidated by using various bioanalytical assays. Radical scavenging activities of compounds 10–24 were evaluated by means of DPPH and ABTS+ scavenging activities. In addition, reducing ability of 10–24 were determined by Fe3+, Cu2+, and [Fe3+-(TPTZ)2]3 reducing activities. α-Tocopherol, trolox, BHA, and BHT were used as positive antioxidant and radical scavenger molecules. On the other hand, IC50 values were calculated for DPPH, ABTS+ scavenging, and AChE inhibition effects of novel compounds. The results obtained from the current studies clearly show that novel bromophenol derivatives 20–24 have considerable antioxidant, antiradical, and AChE inhibition effects.

ChemInform Abstract: Bromolactonization of Alkenoic Acids Mediated by V2O5 via Bromide to Bromenium in situ Oxidation.

Abstract An efficient protocol for the bromolactonization of alkenoic acids is presented that obviates the use of molecular bromine or exogenous bromenium sources. Vanadium (V) oxide catalyzes the in situ oxidation of bromide salts to bromenium (Br + ) in a process mediated by urea–hydrogen peroxide complex. Initial mechanistic investigations indicate that the presence of urea does not accelerate the halolactonization reaction.

Solvatochromic shifts of Br₂ and I₂ in water cages of type 5¹², 5¹²6², 5¹²6³, and 5¹²6⁴.

Despite the relatively small size of molecular bromine and iodine, the physicochemical behavior in different solvents is not yet fully understood, in particular when excited-state properties are sought. In this work, we investigate isolated halogen molecules trapped in clathrate hydrate cages. Relativistic supermolecular calculations reveal that the environment shift to the excitation energies of the (nondegenerate) states 3Πu and 1Πu lie within a spread of 0.05 eV, respectively, suggesting that environment shifts can be estimated with scalar-relativistic treatments. As even scalar-relativistic calculations are problematic for excited-state calculations for clathrates with growing size and basis sets, we have applied the subsystem-based scheme frozen-density embedding, which avoids a supermolecular treatment. This allows for the calculation of excited states for extended clusters with coupled-cluster methods and basis sets of triple-zeta quality with additional diffuse functions mandatory for excited-state properties, as well as a facile treatment at scalar-relativistic exact two-component level of theory for the heavy atoms bromine and iodine. This simple approach yields scalar-relativistic estimates for solvatochromic shifts introduced by the clathrate cages.

In vitro antiproliferative/cytotoxic activity of 2,3ʹ-biindole againstvarious cancer cell lines

2,3'-Biindole (2) was synthesized via bromination of indole (1) with molecular bromine and underwent simultaneous dimerization. Antiproliferative and cytotoxic activity of 2 was investigated in vitro on C6 (rat brain tumor), HeLa (human cervix carcinoma), and HT29 (human colon carcinoma) cells lines by using BrdU cell proliferation ELISA and lactate dehydrogenase (LDH) assays. In contrast to 5-fluorouracil (5-FU), 2,3'-biindole (2) significantly inhibited proliferation of HeLa and HT29 cell lines. According to LDH assay, the cytotoxicity of compound 2 was low on HT29 cell lines and high on HeLa and C6 cell lines. Moreover, 2 did not cause any DNA laddering on the DNA of tested cells; therefore, it is suggested that the mechanism of action of this compound may not involve apoptosis. In addition, 2 inhibited relaxation of supercoiled plasmid DNA by topoisomerase activity. Results of the present study indicates that biindole (2) may have promising anticancer and antitopoisomerase potential with an unknown mechanism of action.

Quantum Topology of the Charge Density of Chemical Bonds. QTAIM Analysis of the C-Br and O-Br Bonds

The present study aims to explore the quantum topological features of the electron density and its Laplacian of the understudied molecular bromine species involved in ozone depletion events. The characteristics of the C-Br and O-Br bonds have been analyzed via quantum theory of atoms in molecules (QTAIM) analysis using the wave functions computed at the B3LYP/aug-cc-PVTZ level of theory. Quantum topology analysis reveal that the C-Br and O-Br bonds show depletion of charge density indicating the increased ionic character of these bonds. Contour plots and relief maps have been analyzed for regions of valence shell charge concentrations (VSCC) and depletions (VSCD) in the ground state.

Microreactor-Mediated Benzylic Bromination in Concentrated Solar Radiation

Sunlight-induced bromination of benzylic compounds was conducted in a capillary microreactor, resulting in mono-brominated compounds with yields of up to 94 %. These reactions can be considered to be eco-friendly since they were carried out without an artificial light source or additional temperature control. In addition, up to 257.9 mmol could be produced daily using cost-effective molecular bromine, which leads to potential improvement of industrial processes.

Tris(2-hydroxyethyl)ammonium 4-halo-2-methylphenoxyacetates (halocresacins)

Convenient and efficient procedures have been developed for the synthesis of tris(2-hydroxyethyl)-ammonium 4-halo-2-methylphenoxyacetates (halocresacins). 4-Chloro-2-methylphenoxyacetic acid necessary for the preparation of chlorocresacin has been obtained by chlorination of 2-methylphenoxyacetic acid with sulfuryl chloride in the presence of aluminum powder. Bromocresacin has been synthesized by reaction of triethanolamine with 4-bromo-2-methylphenoxyacetic acid prepared by bromination of 2-methylphenoxyacetic acid with molecular bromine. Fluoro- and iodocresacins have been synthesized by exchange reaction of chlorocresacin with potassium fluoride and sodium iodide, respectively.

Kinetics and mechanism of CH3Br, CHF2Br, and C2HF4Br photolysis in the presence of dioxygen under the action of λ = 253.7 nm light

The photolysis of CH3Br, CHF2Br, and C2HF4Br mixed with oxygen under radiation emitted by a bactericidal mercury lamp (radiation intensity maximum at λ = 253.7 nm) has been investigated. Oxygen was added in order to simulate natural conditions. A photolysis mechanism has been suggested, the corresponding model calculations have been carried out, and the calculated data have been compared with experimental data. The calculated absorption cross sections are in agreement with the literature, thus proving the validity of the mechanism suggested. The ratios between the rate constants of the reactions of the photolytically generated CH3, CHF2, and C2HF4 radicals with molecular bromine and oxygen have been determined.