· (MW 159.81)
(powerful brominating and oxidizing agent; can initiate/participate in ring cleavage and rearrangement)
Physical Data: mp -7 °C; bp 59 °C; d 3.12 g cm-3.
Solubility: sol H2O, acetic acid, alcohol, ether, chloroform, carbon tetrachloride, carbon disulfide, hydrocarbon solvents (pentane, petroleum ether).
Form Supplied in: dark, red-brown, volatile liquid; also available as a 1 M solution in carbon tetrachloride.
Analysis of Reagent Purity: by iodometric titration.79
Purification: several methods have been described.80
Handling, Storage, and Precautions: bromine is an extremely corrosive and toxic reagent in both liquid and vapor form. As a liquid, it produces painful burns and blisters when spilled on the skin. Such burns should be flushed with water and neutralized with a 10% solution of sodium thiosulfate in water. Medical attention should be sought immediately. Protective clothing is therefore a must, including laboratory coat and apron, protective gloves, and a full-face respirator equipped with a NIOSH-approved organic vapor-acid gas canister. Bromine should be stored in a cool, dry area. It is incompatible with combustibles, liquid ammonia, alkali hydroxides, metals (including aluminum, mercury, magnesium, and titanium), and some types of rubber and plastic.2 Use in a fume hood.
Bromine is a very powerful brominating agent that has found utility in a variety of systems. While the bromination of alkanes is usually not a viable synthetic method,3 alkylbenzenes can be brominated at the benzylic position under radical conditions (eq 1).4 N-Bromosuccinimide (NBS) can also be used for this transformation.
Electrophilic aromatic substitution occurs in the presence of Lewis acids to provide brominated aromatics.5 Monobromination usually occurs due to the deactivating nature of the bromine. However, highly reactive aromatics, such as phenols, anilines, and polyalkylbenzenes, are frequently polybrominated, even in the absence of catalysts.
Bromine has been used in the bromination of heterocycles. However, the unique reactivity patterns of each heterocyclic ring system create a discussion beyond the scope of this review. The reader is directed to reviews on the subject.1a,6
The addition of bromine to alkenes7 proceeds with formation of the cyclic bromonium ion (1), which can then be intercepted by an anionic species (Y-), to give the product derived from anti addition (eq 2). In the case of bromine itself, this gives rise to trans vicinal dibromides (eq 2; Y = Br). Variations from ideality are not uncommon due to weakened, unsymmetrical bridging in the bromonium ion (eq 3),8 transannular interactions (eq 4),9 and substrates susceptible to rearrangements. Brominations in the presence of crown ethers10 and zeolites11 have been investigated to improve selectivity. Conjugated dienes give predominantly 1,4-addition, while alkynes are less susceptible to electrophilic attack.12
The addition of bromine to alkenes has been used as the first step in the oxidation of alkenes to 1,3-butadienes (eqs 5 and 6).13,14 Alkenes can also be protected15 or purified16 by bromination and subsequent regeneration of the double bond.
Alkenes bearing an electron-withdrawing group at one terminus are frequently converted to the a-bromo analogs via a bromination/dehydrobromination sequence (eqs 7 and 8).17,18
Cyclic bromonium ions (1) can be opened by a variety of other nucleophiles. Thus bromination of alkenes in aqueous systems can lead to bromohydrins. However, NBS has been shown to be superior to bromine for this transformation, presumably due to the minimization of competing bromide ion in the reaction mixture.19 Alcohols react to give vicinal bromo ethers, in both inter- and intramolecular fashion (eq 9).20
Bromolactonization of alkenic acids has been the subject of extensive investigation.21 Cyclizations can be performed on the carboxylic acid salts as well as the free acids. Thallium(I) salts have proven to be especially efficacious.21b,22 Treatment of the mercury(II) salts with bromine proceeds via a radical mechanism and provides the expected products in substrates where normal bromolactonization conditions lead to rearrangement (eq 10).23 Other sources of electrophilic bromine can also give different products (eq 11).21b
The enol lactonization of alkynic acids can be performed to give either the (E)- or (Z)-bromo enol isomers depending on reaction conditions (eq 12).24
Alkenic amides cyclize under standard conditions to form lactones rather than lactams.25 Bromolactamization can be achieved, however, by introduction of substituents on the amide nitrogen that serve to lower its pK
a (eqs 13 and 14).26,27
Electron-rich alkenes, such as enol ethers28 and enamines,29 can be brominated to furnish the b-bromo compounds (eq 15).
Bromine has been used for brominations a to carbonyl groups.30 Carboxylic acids are brominated in the presence of phosphorus or phosphorus trihalides in the classical Hell-Volhard-Zelinski reaction (eq 16).31 Variations on this include brominations in thionyl chloride32 and in polyphosphoric acid.33 The less reactive carboxylic esters are frequently converted to the acid halide, a-brominated, and subsequently re-esterified in one pot.34,35
The bromination of ketones is believed to occur via acid-catalyzed enolization, followed by electrophilic attack on the enol form.30 Unsymmetrical ketones can give rise to mixtures of bromo ketones due to mixtures of enols, and several approaches to overcome this shortcoming have been reported. Radical bromination in the presence of epoxides (as acid scavengers) allows for substitution at the more highly substituted position (eq 17).36 Silyl enol ethers of aldehydes and ketones react with bromine (or NBS) to give the a-brominated carbonyl compounds (eq 18).37 This, combined with the ability to regiospecifically prepare silyl enol ethers (kinetic vs. thermodynamic), makes for an extremely useful technique for the preparation of a-bromo carbonyl compounds.
Sulfoxides are best a-brominated with a combination of bromine and NBS in pyridine.38
Bromine has been used in the halogenation of organometallic reagents. Organomagnesium,39 organolithium,40 and organoaluminum41 reagents react to give the compounds in which the metal has been replaced by bromine. Organoboranes can react with bromine in several ways. Bromination in the presence of sodium methoxide gives the corresponding alkyl bromides.42 Photobromination (in the absence of strong base) gives an initial a-bromo organoborane that can either give the corresponding alkyl bromide43 or rearrange to a new organoborane.44 Organoboranes can also be converted to alkyl bromides in aqueous media.45 Alkenic bromides have been prepared from alkenylboronic esters with inversion of configuration (eq 19).46
Enolates of ketones47 and esters48 can be brominated by treatment with bromine (eq 20), as can the anions of terminal alkynes.49 The high reactivity of bromine, however, is sometimes a problem; milder sources of electrophilic bromine (such as 1,2-Dibromoethane) are occasionally used in its place.
Bromine reacts with secondary alcohols to give ketones. Since ketones are subject to bromination themselves (see above), the a-bromo ketones can sometimes be undesirable byproducts. However, in cases where there are no a-protons, this can provide an excellent method of oxidation (eq 21).50
Primary alcohols are oxidized to either aldehydes or, more commonly, esters. An especially attractive corollary to this involves the oxidation of acetals to esters (eq 22).51
The addition of coreactants has provided a number of selective bromine-based oxidants. Both bromine/Hexamethylphosphoric Triamide (HMPA)52 and bromine/Bis(tri-n-butyltin) Oxide (HBD)53 have shown a preference for the oxidation of secondary vs. primary alcohols (eq 23), while bromine/nickel carboxylates54 convert 1,4-diols to g-butyrolactones by selective oxidation of the primary alcohols (eq 24).
Tetrahydrofurans have been prepared from alcohols or diols by bromine/silver(I) salts (eq 25)55 or bromine/DMSO,56 respectively.
Bromine has demonstrated its superiority in the oxidation of enediol bis-trimethylsilyl ethers to a-diketones (eq 26).57
A number of other functional groups are oxidized by bromine; however, they do not appear to have gained widespread use. These include cyclohexenones,58 ethers,59 hydrazines,60 oximes,61 tertiary amines,62 thiols,63 sulfides,64 and organoselenium reagents.65
Bromine reacts with a number of functional groups to effect bond cleavage or other skeletal rearrangements. In the classical Hofmann rearrangement,66 treatment of primary amides with bromine in the presence of base gives isocyanates, carbamates, or amines, depending on the reaction conditions (eq 27).67
In the Hunsdiecker reaction,68 treatment of silver salts of carboxylic acids with bromine furnishes the alkyl(aryl) bromides with one less carbon atom. Improvements that do not require the preparation of the dry silver salts include the use of mercury(II) salts (Cristol-Firth modification) (eq 28),69 thallium(I) salts,70 and photostimulation.71
Three-membered rings are especially susceptible to reaction with bromine. Cyclopropanes are opened to give 1,3-dibromopropanes,72 while cyclopropenylethanol derivatives rearrange in the presence of bromine to give 3-methylenetetrahydrofurans (eq 29).73 Trimethylsilyl cyclopropyl ethers are opened to give b-bromo ketones (eq 30).74 Epoxides can give either bromohydrins75 or a-bromo ketones,76 depending on the reaction conditions.
Mercury(II)-mediated cyclization of dienes allows access to bromine-containing natural products.77 Thus, in the synthesis of aplysistatin, the key step was the cyclization of an acyclic precursor to the required bromoperhydrobenzoxepine ring system (eq 31).78
Pyridinium Hydrobromide Perbromide;
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R. Richard Goehring
Scios Nova, Baltimore, MD, USA
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