Formation of Halohydrins

Propose mechanisms and predict the major products of the following reactions. Include stereochemistry where appropriate. 

Models may be helpful whenever stereochemistry is invoived. Write compiete structures, inciuding aii bonds and charges, when writing mechanisms. 

A halohydrin is an alcohol with a halogen on the adjacent carbon atom. In the pres- 8-9 

Step 2 Water optens the halonium ion deprotonation gves the halohydria 

Step 2 Back-side attack by water opens the chloronium ion. 

An aqueous solution of bromine or chlorine reacts with alkenes to form addition products called halohydrins. These compounds have a halogen and a hydroxyl group on adjacent carbon atoms. The reaction of aqueous chlorine with propene is shown below. 

Give the structure of the product formed when 2-methyl-1-butene reacts with bromine in aqueous solution. 

Carbenes have a formal charge of zero because the unshared electron pair in the sp -hybridized orbital belongs to the carbon atom. Like a carbocation, a carbene is a highly reactive, electrophilic intermediate because it has only six electrons in its valence shell. 

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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. 

Table 9. CPO-catalyzed formation of halohydrins from olefins ...

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). 

Formation of Halohydrins from Epoxides (3) OC-seco-Halo-de-alkoxylation... 

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... 

Mechanism 8-7 Addition of Halogens to Alkenes 350 8-9 Formation of Halohydrins 352... 

Mechanism 8-8 Formation of Halohydrins 352 8-10 Catalytic Hydrogenation of Alkenes 355 8-11 Addition of Carbenes to Alkenes 358 8-12 Epoxidation of Alkenes 360... 

CHAPTER 8 Ionic Addition of HX to an Alkene 332 Free-Radical Addition of HBr to Alkenes 334 Acid-Catalyzed Hydration of an Alkene 338 Oxymercuration of an Alkene 340 Hydroboration of an Alkene 345 Addition of Halogens to Alkenes 350 Formation of Halohydrins 352 Epoxidation of Alkenes 360 Acid-Catalyzed Opening of Epoxides 362 Olefin Metathesis 376... 

The formation of halohydrins can be promoted by peroxidase catalysts.465 Recently 466 it has been shown that photocatalysis reactions of hydrogen peroxide decomposition in the presence of titanium tetrachloride can produce halohydrins. The workers believe that titanium(IV) peroxide complexes are formed in situ, which act as the photocatalysts for hydrogen peroxide degradation and for the synthesis of the chlorohydrins from the olefins. The kinetics of chlorohydrin formation were studied, along with oxygen formation. The quantum yield was found to be dependent upon the olefin concentration. The mechanism is believed to involve short-lived di- or poly-meric titanium(IV) complexes. 

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... 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

The reaction of Grignard reagents with epoxides, at first glance, appears to be an effective method for a two-carbon homoligation. However, there are several competing reactions that limit the use of this method. These deleterious reactions are formation of halohydrins, rearrangements, polymerization of the epoxide, and in asymmetric epoxides, regioselectivity issues. 

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... 

The major biotransformation pathway involves an oxidative step with introdnction of an oxygen atom and subsequent formation of halohydrin. The unstable halohy-drin loses hydrobromic acid to yield trifluoroacetyl chloride, which in turn is hydrolyzed to trifluoroacetic acid. This final metabolite is fonnd in the nrine. °... 

Addition of HOX by means of A-halo amides is important for, inter alia, steroid syntheses. A 9(ll)-double bond adds OH at position 11 (11/S-OH) and Br at position 9 (9oc-Br). Solvents used are mixtures of water with acetone, dioxane, pyridine, or tert-butyl alcohol. 0.46N-perchloric acid has proved particularly suitable as acid since it reduces any tendency to formation of halohydrin esters.295... 

Formation of Halohydrins Step I Electrophilic attack forms a haloniuin ion. 

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