Replacement of bromine

Replacement of bromine in ethyl bromofluoroacetate by thiolate anions occurs easily [44] (equation 40)... 

The reactions shown above are nucleophilic substitutions that involve replacement of bromine by oxygen. The reactions may or may not proceed by similar mechanisms. 

Acetyl-lO,11-dibromo-5//-dibenz[7>,/]azepine (49), formed by addition of bromine to 5-acetyl-5/7-dibenz[7>,/]azepine, undergoes dehydrobromination to the 5-acetyldibenz[7>,/]-azepinc 50a on treatment with ethanolic potassium hydroxide.121-132 In contrast, on heating the dibromo compound under reflux with sodium methoxide in methanol, amide hydrolysis and methoxy denomination occur to give the 10-methoxy derivative 50b.132,1 33 Dehydrobromination of the dibromo compound 49, without hydrolysis or replacement of bromine, can be accomplished in hot dibutylamine.118... 

Halogen exchange of F is usually with chloro compounds however, replacement of bromine has enabled fluorodiazirines to be obtained (83JA6513 86TL419). Diazirine (2) was previously obtained by a difficult route involving F2. The relative ease of access to (2) enables a carbene whose reactivity is intermediate between that of electrophilic ( CF2) and nucleophilic ( C(OMe)2) carbenes to be studied. 

The replacement of established chemistries with newer ones is one of the classic drivers of change in the chemical industry. One of the current hotbeds of this kind of change is the replacement of brominated flame retardants in polymer formulations. The brominated flame retardants under the most scrutiny have been polybrominated diphenyl ethers, particularly penta- and octabromodiphenyl ether, which have been shown to be persistent in the environment and to bioaccumulate. Great Lakes Chemical is voluntarily phasing out penta- and octa-BDEs by the end of next year. The phaseout is made possible by the clean bill of health granted by EPA for Firemaster 550, a replacement for penta-BDE in flexible PU applications. BRG Townsend claims the phaseout of penta-BDE and octa-BDE is not as earth shattering as would be an exit from deca-BDE, a styrenics additive that is produced in the highest volume of the PBDEs. 

The second and third steps in the monomer synthesis involve the replacement of bromine with an acetylene protected by an acetone adduct, followed by cleavage of the adduct. These steps will be discussed in more depth later as they are the same for systems containing only monomer or a monomer/oligomer mixture. 

The monomer/oligomer mixtures were used In the third step of the reaction sequence, the replacement of bromine with 2-methyl-3-butyn-2-ol by use of the bls(trlphenylphosphlne) palladium chloride catalyst system. This reaction used a trlethylamine/pyridine solvent system to replace the bromines on the ether sulfone with ethynyl groups protected by acetone adducts. The acetone protecting groups were then removed In a toluene/methanol/potasslum hydroxide solvent system. 

Mixed trialkylstannyl and silyl derivatives have also been used in coupling reactions, with subsequent replacement of the silyl substituent by bromine, leading to species that are capable of undergoing further coupling reactions. This process was amply demonstrated by the recent synthesis of micrococcinic acid 203, which involved four palladium-catalyzed crosscoupling reactions on stannylated substrates, two palladium-catalyzed trimethylstannane replacements of bromine, two trimethylsilyl displacements by bromine, and a total of four bromine-lithium exchange reactions, on three different thiazole derivatives and one pyridine derivative (91-TL4263). 

Bugge brominated thienothiophenes 1 and 2 with IV-bromo-succinimide in glacial acetic acid to 2-bromothieno[2,3-6]thiophene (66%) and 2-bromothieno[3,2-6]thiophene (55%). The structure of 2-bromothieno[2,3-6]thiophene was confirmed by the replacement of bromine by lithium at —70° followed by carbonation to thieno[2,3-6j-thiophene-2-carboxylic acid 2-bromothieno[3,2-fe]thiophene was independently prepared by the treatment of 2-lithiothieno[3,2-6]thiophene with one equivient of bromine at —70°. The 2-bromo derivatives of thienothiophenes 1 and 2 decompose within several hours at 20°, but remain uncWged for weeks at —15°. 

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

Bromine trifluoride, neat or dissolved in liquid bromine, has found application for the selective substitution of fluorine for bromine (Table 3).108,109 The reactions are carried out at temperatures of no more than 60 C. Under these conditions no hydrogen substitution is observed. As established for bromofluoroethanes. the relative ease of replacement of bromine in various groups decreases in the order tribromomethyl > dibromofluoromethyl > dibromomethyl > bromofluoromethyl > bromomethyl. The presence of fluorine at either the same or an adjacent carbon tends to retard the substitution. Bromine trifluoride is more effeetive than antimony fluorides as it replaces bromine in bromodifluoromethyl and bromomethyl groups. 

The synthetic utility of many of the substitution reactions described so far is limited because there are well-established thermal routes to the same products. However, a third group of photochemical nucleophilic substitutions involves aryl halides and nucleophiles based on sulfur, phosphorus or, of particular importance, carbon. Two examples are the reaction of bromobenzene with the anion of t-butyl methyl ketone 13.12), and the replacement of bromine by cyanomethyl in 2-bromopyridine (3.13). This type of reaction offers a clear advantage over lengthy thermal alternatives, and intramolecular versions have been used in the synthesis of indoles (e.g. 3.14) or benzofurans from o-iodoaniline or o-iodoanisole respectively. 

Stannylenes are oxidized to keto-alcohols by dropwise addition of bromine in di-chloromethane. The reaction proceeds at room temperature at the speed of a titration. The attention of chemists who want to check their reaction by infrared (IR) examination in situ is drawn to the fact that the ketone may be chelated to tin in these conditions (vqj 1685 cm-1). The reaction is regiospecific, giving only one of the two possible keto-alcohols. It has been used in total synthesis for instance, in the synthesis of (+)-spectinomycin (described under Sec. QI.G) [12,13]. The replacement of bromine by IV-bromosuccinimide as oxidant has been reported [14]. 

Only a few exchange reactions of substituents directly bound to the heterocyclic ring have been reported. Gompper has studied the nucleophilic substitution of bromo- and chloro-l,2,3-triazines and observed replacement of bromine or chlorine with sodium ethoxide, sodium ethanethiolate and amines. In most cases yields are quantitative. With the trihalo compound, first the 4-mono- then the 4,6-di-substituted derivative is obtained (79CB1529). Reaction of 5-chloro-2-methyl-4,6-bis(dimethylamino)-l,2,3-triazinium iodide (61) with malononitrile affords compound (62). Compounds of the general structure (63) are hydrolyzed to l,2,3-triazin-5(2//)-ones (64) (79CB1535). 

Exercise 14-12 Would you expect 4-bromonitrobenzene or (4-bromophenyl)-tri-methylammonium chloride to be more reactive in bimolecular replacement of bromine by ethoxide ion Why ... 

The photocyclizations of halogenated A-benzyl-/ -phenethylamines576 are examples of reactions in which two aryl rings are connected by a chain of four atoms, one of which is a nitrogen atom. In the cases reported, one phenyl ring has a bromine atom and the other an iodine atom at the ortho position. As expected, products were formed via initial rupture of the carbon-iodine bond and these products still contained the bromine atom. In addition, however, some unexpected cyclization products were encountered, containing iodine instead of bromine. The formation of these products was ascribed to replacement of bromine by iodine in the intermediate cyclohexadienyl radicals. 

Other inorganic metathetical exchange reactions studied include the replacement of bromine by fluorine and chlorine in N3P3Br6 and the preparation of azido-, cyano-, and isothiocyanatocyclophospha-zenes (21, 22, 249). In the reactions of N3P3C16 with KF and KSCN, addition of [18-Crown-6]ether considerably enhances the yields of substituted cyclophosphazenes, N3P3R6 (R = F, NCS) (449). 

Table 3. Kinetic parameters of SN2-replacement of bromine in ethyl-and benzylbromid by anion (II)...

Experimentally found energy of activation SN2 of replacement of bromine in methylbromid and benzylbromid by anion (II) and aniones (V a), (V b) (tables 3, 6) according to equation Arrenius correlate with sizes of the power barriers designed by a method ab-initio (rice 1). 

Bromine trifluoride or chlorine Irifluoride in bromine solution reacts smoothly with bromo-fluoroctlnmes to give a progressive substitution of bromine by fluorine, e.g. formation of 25. The relative case of the replacement of bromine in various groups was shown to be CBr, > CBfjF > CHBr, > CBrF, > CHBrF > CH,Br. 

Vinylic bromine can be replaced fairly easily without reduction of the double bond. This is a characteristic difference from hydrogenolysis of vinylic chlorine and especially fluorine. Catalytic hydrogenation of ethyl a-methyl-3-bromocrotonate resulted in replacement of bromine and formation of ethyl a-methylcrotonate (equation 15). In 14-bromocodeinone (9), replacement of bromine occurs with a double bond shift to give neopinone (10 equation 16).4... 

Isopropyl alcohol under UV irradiation converts bromobenzene to benzene in 72% yield (Table 4). Similar replacement of bromine by hydrogen is accomplished by treatment of aryl bromides dissolved in dichloromethane with a mixture of ethanethiol and anhydrous aluminum chloride. This hard acid-soft base combination reacts with polycyclic aromatic halides and halogenated phenols by an addition-elimination mechanism, leading to an aryl ethyl sulfide through a radical anion intermediate. This is converted by another molecule of ethanethiol to the debrominated arene and diethyl disulfide. 1-Bro-monaphthalene is thus transformed into naphthalene (equation 59), 2,4,6-tribromophenol into phenol (equation 60), and bromochlorophenols into chlorophenols in 61-91% yields. ... 

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