Halogenation and Halohydrin Formation

BINAP does not have a chirality center, but nevertheless, it is a chiral compound because the single bond joining the two ring systems does not experience free rotation (as a result of steric hindrance). BINAP can be used as a chiral ligand to form a complex with ruthenium, producing a chiral catalyst capable of achieving very pronounced enandoselectivity  

Halogenation involves the addition of X2 (either Br2 or CI2) across an alkene. As an example, consider the chlorination of ethylene to produce dichloroethane  

This reaction is a key step in the industrial preparation of polyvinylchloride (PVC) r 

Halogenation of alkenes is only practical for the addition of chlorine or bromine. The reaction with fluorine is too violent, and the reaction with iodine often produces very low yields. 

The stereospecificity of halogenation reactions can be explored in a case where two new chirality centers are formed. For example, consider the products that are formed when cyclopen-tene is treated with molecular bromine (Br2)  

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Anti addition occurs in halogenation and halohydrin formation. 

The final product is called a halohydrin (indicating that we have a halogen— Br— and an OH in the same compound). This reaction is commonly called halohydrin formation. 

Electrophilic addition of the halogens and related X—Y reagents to alkenes and alkynes has been a standard procedure since the beginning of modem organic chemistry.1 Anti electrophilic bromination of such simple compounds as cyclohexene and ( )- and (Z)-2-butene, and variants of this reaction when water or methanol are solvents (formation of halohydrin or their methyl ethers, respectively), are frequently employed as prototype examples of stereospecific reactions in elementary courses in organic chemistry. A simple test for unsaturation involves addition of a dilute solution of bromine in CCU to the... 

The Markovnikov orientation observed in halohydrin formation is explained by the structure of the halonium ion intermediate. The two carbon atoms bonded to the halogen have partial positive charges, with a larger charge (and a weaker bond to the halogen) on the more substituted carbon atom (Figure 8-5). The nucleophile (water) attacks this more substituted, more electrophilic carbon atom. The result is both anti stereochemistry and Markovnikov orientation. 

Peracid epoxidation and indirect epoxidation via the halohydrin route normally display opposite diastereoselectivity. In the indirect epoxidation route, the steric course is normally controlled by the first step, the formation of the most stable halonium ion, and not by the second step, the (tranx-diaxial) attack by the (nucleophilic) oxygen species. However, the relative rates and equilibria of both steps depend on the source of positive halogen and the reaction conditions which strongly influence the obtained stereoselectivity (Tables 3 and 4, and Section 4.5.1.1.3,). 

The mechanism for halohydrin formation is similar to the mechanism for halogenation addition of the electrophile X (from X2) to form a bridged halonium ion, followed by nucleophilic attack by H2O from the back side on the three-membered ring (Mechanism 10.4). Even though X is formed in Step [1] of the mechanism, its concentration is small compared to H2O (often the solvent), so H2O and not X" is the nucleophile. 

How can the orientation of the halogen and hydroxyl be explained in these reactions For example, in propylene chlorohydrin, the chlorine is attached to the terminal carbon, not the middle one. This orientation, and the others, can be accounted for by the mechanism of halohydrin formation. It involves intermediate carbonium ions. 

CH3CH=CH2, and allow halohydrin formation to occur with Br and NaOH at 25°. Addition of bromine (or chlorine) with water or sodium hydroxide results in compounds containing halogen and hydroxyl groups on adjacent carbon atoms. The reaction is ... 

The first step is the same as that for halogen addition. In the second step, however, the two mechanisms differ. In halohydrin formation, water acts as the nucleophile and attacks one carbon atom of the halonium ion. The three-membered ring opens, and a protonated halohydrin is produced. Loss of a proton then leads to the formation of the halohydrin itself. 

The reactions of the cyclitols with halogen acids may be divided into two groups, halohydrin formation and aromatization. 

Like the acid-catalyzed hydration of alkenes and the reaction of alkenes with hydrogen hahdes, halohydrin formation is regioselective. The halogen bonds to the less substituted carbon of the double bond and hydroxyl to the more substituted carbon. 

There are a number of biological examples of halohydrin formation, particularly in marine organisms. As with halogenation (Section 8.2), halohydrin formation is carried out by haloperoxidases, which function by oxidizing Br or Cl ions to the corresponding HOBr or HOCl bonded to a metal atom in the enzyme. Electrophilic addition to the double bond of a substrate molecule then yields a bromonium or chloronium ion intermediate, and reaction with water gives the halohydrin. For example ... 

If the reaction on the previous page is carried out in the presence of a large excess of another nucleophile (e.g., H2O), this other nucleophile will out-compete Br . Show a possible mechanism (via a carbocation intermediate) for formation of the halohydrin shown below, (halohydrin = a molecule with a halogen and an OH on adjacent carbons)... 

The activities of both haloalkanol dehalogenase (halohydrin hydrogen lyase) that catalyzes the formation of epoxides from alkanes with vicinal hydroxyl and halogen groups, and epoxide hydrolase that brings about hydrolysis of epoxyalkanes to diols are involved in a number of degradations that involve their sequential operation. 

Haloperoxidases act as halide-transfer reagents in the presence of halide ions and hydrogen peroxide. In the first step, the halide ion is oxidized to a halonium-ion carrier, from which the positive halogen species is then transferred to the double bond. In an aqueous medium, the intermediary carbocation is trapped and racemic halohydrins are formed (Eq. 7). Selective examples of CPO-cata-lyzed formation of halohydrins are given in Table 9. In CPO-catalyzed reaction. 

Peroxidases catalyze not only the formation of halohydrines, but also the halo-genation of 1,3-dicarbonyl compounds. In CPO-catalyzed halogenation of eno-lizable substrates, the halonium ion is trapped by the enolate to afford the corresponding mono- and dihalogenated products (Eq. 9, Table 10). 

Electrooxidation of halide salts is quite useful for the generation of reactive species of halogen atoms under mild conditions. Functionalization of alkenes involving the formation of halohydrins, 1,2-halides, a-halo ketones, epoxides, allylic halides and others has been achieved by electrochemical reactions and is well documented in the literature. On the other hand, electrogenerated carbenium ions can be captured by nucleophilic halide anions, providing a new route to halogenated compounds... 

Synthesis of Epoxides from Chiral Chlorohydrins. Asymmetric halogenation of CSA-derived esters allows for the formation of enantiomerically pure halohydrins and terminal epoxides (eq 23). ... 

One further point. We have encountered the two-step addition of unsym-metrical reagents in which the first step is attack by positive halogen formation of halohydrins (Sec. 6.14), and ionic addition of IN3 and BrN3 (Problem 7, p. 247). The orientation is what would be expected if a carbonium ion were the intermediate. Propylene chlorohydrin, for example, is CH3CHOHCH2CI IN3 adds to terminal alkenes to yield RCH(N3)CH2l. Yet the exclusively anti stereochemistry... 

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