Halohydrin stereochemistry

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

HC1, HBr, and HI add to alkenes by a two-step electrophilic addition mechanism. Initial reaction of the nucleophilic double bond with H+ gives a carbo-cation intermediate, which then reacts with halide ion. Bromine and chlorine add to alkenes via three-membered-ring bromonium ion or chloronium ion intermediates to give addition products having anti stereochemistry. If water is present during the halogen addition reaction, a halohydrin is formed. 

Bartnicki EW, CE Castro (1969) Biodehalogenation. The pathway for transhalogenation and the stereochemistry of epoxide formation from halohydrins. Biochemistry 8 4677-4680. 

Alkyl and acyl hypohalites, when adding to carbon-carbon double bond, afford halohydrin ethers and esters, respectively.151 Regioselective and syn stereoselective addition of CF3OF, CF3CF2OF, and CF3COOF to stilbenes was reported.152-154 The stereochemistry was explained to originate from the formation and immediate... 

The mechanism and stereochemistry of halogenation, physical methods / 273 Dihalogenation / 276 The use of A-halo compounds / 280 The use of other reagents / 282 The oxidation of halohydrins / 283 Vinylogous a-halo ketones / 284... 

Figure 11.5 shows a mechanism that has been postulated for this reaction. First, an electrophilic mercury species adds to the double bond to form a cyclic mercurinium ion. Note how similar this mechanism is, including its stereochemistry and regiochemistry, to that shown in Figure 11.4 for the formation of a halohydrin. The initial product results from anti addition of Fig and OH to the double bond. In the second step, sodium borohydride replaces the mercury with a hydrogen with random stereochemistry. (The mechanism for this step is complex and not important to us at this time.) The overall result is the addition of H and OH with Markovnikov orientation. 

Stereochemistry of Halohydrin Formation Because the mechanism involves a halonium ion, the stereochemistry of addition is anti, as in halogenation. For example, the addition of bromine water to cyclopentene gives fran.v-2-bromocyclopentanol, the product of anti addition across the double bond. 

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. 

Synthesis of Optically Active Epoxides. Alkaloids and alkaloid salts have been successfully used as catalysts for the asymmetric synthesis of epoxides. The use of chiral catalysts such as quinine or quinium benzylchloride (QUIBEC) have allowed access to optically active epoxides through a variety of reaction conditions, including oxidation using Hydrogen Peroxide (eq 5), Darzens condensations (eq 6), epoxidation of ketones by Sodium Hypochlorite (eq 7), halohydrin ring closure (eq 8), and cyanide addition to a-halo ketones (eq 9). Although the relative stereochemistry of most of the products has not been determined, enan-tiomerically enriched materials have been isolated. A more recent example has been published in which optically active 2,3-epoxycyclohexanone has been synthesized by oxidation with t-Butyl Hydroperoxide in the presence of QUIBEC and the absolute stereochemistry of the product established (eq 10). ... 

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... 

A notable feature of the halohydrin route is that it makes available epoxides with the stereochemistry opposite of that obtained using peroxy acids. 

Q3. When bromine is added to an alkene in solution in CC14, a dibromide is produced. Explain why, when bromine is added to the alkene 1 in aqueous solution, the product is a halohydrin, i.e. HO and Br have been added to adjacent atoms. What is the nature and stereochemistry of the product ... 

The activation of a diol function could be performed in many different ways. As will be discussed later, vicinal diols can be easily transformed into epoxides, halohydrins and cyclic sulfates, all of them reacting readily and with high stereocontrol with a range of nucleophiles. An intermediate typically generated during the formation of cyclic sulfates [113] is the corresponding cyclic sulfite (Scheme 37). Several nucleophiles, e.g. N3, Cl and Br react readily with activated cychc sulfites to afford in good yield and with clean inversion of stereochemistry, the substitution products. 

In contrast to this result, Zimmerman and Ahramjian have reported that treatment of the halohydrin (9 a single diastereomer, unknown relative stereochemistry) with potassium f-butoxide in the presence of m-nitrobenzaldehyde affords only the glycidic ester (10 equation 4), indicating that in this case the rate-limiting step is cyclization. ... 

Generation of the sulfinyl carbanion of chloromethylphenyl sulfoxide (Bu"Li/THF, -78 °C), followed by treatment with cyclohexanone, acetone or benzophenone, affords the corresponding chlorohydrin (27) in good yield (68-79%). Treatment of the cyclohexanone or acetone adducts with methanolic KOH provides the a, 3-epoxy sulfoxides in yields of greater than 90% (Scheme 7). Each of the halohydrin products appeared to be a single diastereomer, although the relative stereochemistry was not assigned. 

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