Hydration by oxymercuration-demercuration

Many alkenes do not easily undergo hydration in aqueous acid. Some alkenes are nearly insoluble in aqueous acid, and others undetgo side reactions such as rearrangement, polymerization, or charring under these strongly acidic conditions. In some cases, the overall equilibrium favors the alkene rather than the alcohol. No amount of catalysis can cause a reaction to occur if the energetics are unfavorable. 

Oxymercuration-demercuration is another method for converting alkenes to alcohols with Markovnikov orientation. Oxymercuration-demercuration woiks with many alkenes that do not easily undetgo direct hydration, and it takes place under milder conditions. No free carbocation is formed, so there is no opportunity for rearrangements or polymerization. 

The reagent for meieuration is mercuric acetate, Hg(OCOCH3)2, abbreviated Hg(OAc)2- There are several theories as to how this reagent acts as an electrt hile the simplest one is that mercuric acetate dissociates slightly to form a positively charged mercury species, Hg(OAc). 

Oxymercuration of an Alkene Step I Electrophilic attack forms a mercurinium ion. 

Step 2 Water opens the ring to give an oiganomercurial alcohol. 

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Mechanism 8-4 Acid-Catalyzed Hydration of an Alkene 338 8-5 Hydration by Oxymercuration-Demercuration 340 Mechanism 8-5 Oxymercuration of an Alkene 340 8-6 Alkoxymercuration-Demercuration 342 8-7 Hydroboration of Alkenes 343... 

Mercuric acetate sodium tetrahydridoborate MarkownikofE hydration by oxymercuration-demercuration... 

When the alcohol reactant is also the solvent, the method is called solvomercuration-demercuration. This method directly parallels hydration by oxymercuration-demercuration (Section 8.5) ... 

Hydroboration-oxidation, then, converts alkenes into alcohols. Addition is highly regiospecific the preferred product here, however, is exactly opposite to the one formed by oxymercuration-demercuration or by direct acid-catalyzed hydration. For example ... 

As a consequence, hydroboration-oxidation gives us a method for the preparation of alcohols that cannot normally be obtained through the acid-catalyzed hydration of alkenes or by oxymercuration—demercuration. 

STRATEGY AND ANSWER We recognize that synthesis by path (a) would require a Markovnikov addition of water to the alkene. So, we could use either acid-catalyzed hydration or oxymercuration—demercuration. 

In both SnI and Sn2 reactions, the leaving group is the halogen of an alkyl halide or the sulfonate group of a sulfonate ester. Both alkyl halides and sulfonate esters are prepared from alcohols. In Chapter 10, alcohols were prepared by the hydration reaction of alkenes, by oxymercuration-demercuration of alk-enes, or by hydroboration of alkenes. Other methods can be used to prepare alcohols, and they will be discussed at a later time. This section will describe several of the reactions used to convert alcohols to halides or sulfonate esters. 

Oxymercuration/demercuration provides a milder alternative for the conventional acid-catalyzed hydration of alkenes. The reaction also provides the Markovnikov regiochemistry for unsymmetrical alkenes.33 Interestingly, an enantioselective/inverse phase-transfer catalysis (IPTC) reaction for the Markovnikov hydration of double bonds by an oxymercuration-demercuration reaction with cyclodextrins as catalysts was recently reported.34 Relative to the more common phase-transfer... 

Markownikov hydration of olefins. H. C. Brown and Geoghegan39 report that Markownikov hydration of olefins can be achieved very simply by oxymercuration with mercuric acetate followed by demercuration with sodium borohydridc. 

Hydration of the double bond in 3,4-unsaturated sugars by the oxymercuration-demercuration procedure should lead either to 3- or to 4-deoxy sugars. It was found that this reaction applied to methyl 3,4-dideoxy- and 3,4,6-trideoxy-a-DL-hex-3-enopyranosides proceeded regio- and stereospecifically and furnished methyl 3-deoxy- and 3,6-dideoxy-DL-hexopyranosides. From substrates of the a-erythro configuration only a-xylo products (374) were obtained, a-threo substrates gave products (375) of the lyxo configuration. 

Oxymercuration-demercuration Hydration of a double bond by addition of a mercuric salt and water, then removal of mercury. 

In the oxymercuration process, the electrophilic addition of the mercuric species occurs resulting in a mercurinium ion which is a three-membered ring. This is followed by the nucleophilic attack of water and as the proton leaves, an organomercuric alcohol (addition product) is formed. The next step, demercuration, occurs when sodium borohydride (NaBH ) substitutes the mercuric acetate substituent with hydrogen. If an alkene is unsymmetric, Oxymercuration-demercuration results in Markovnikov addition. The addition of mercuric species and water follows an anti (opposite side) addition pattern. This reaction has good yield, since there is no possibility of rearrangement unlike acid-catalyzed hydration of alkenes. 

The anfi-Markownikoff-hydration of carbon-carbon double bonds hydroboration-oxidation has been supplemented by a remarkably simple and likewise stereospecific Markownikoff-hydration achieved by a one-step oxymercuration-demercuration p-Nitrophenyl chloroformate has been recommended for the protection of hydroxyl groups in nucleosides... 

Steric effects may play a role in the regiochemistry of the reaction as well. While the oxymercuration-demercuration reaction is generally considered to give only Markovnikov hydration, as shown by predominant formation of 43, this regioselectivity is not absolute. For example, methoxymercuration of 3,3-dimethyl-l-butene produced 2% of 3,3-dimethylbutyl methyl ether (44, equation 9.42). ... 

A shorter but less selective route to la-hydroxycholesterol has been described by Kaneko (90). Cholesta-l,4-dien-3-one (90) was deconjugated to its -isomer and then reduced with borohydride to give 3P-hydroxy-cholesta-1,5-diene (91). Selective hydroboration followed by alkaline peroxide treatment afforded a 30% yield of a separable 1 1 mixture of la- and 2a-hydroxycholesterol (89) and (93). If the acetate (92) was hydrated by an oxymercuration-demercuration procedure, a mixture of the 2 3-hydroxycholesterol (94) (14%) and la-hydroxycholesterol (89) (26%) was isolated after saponification (118). When starting with the readily available cholesta-l,4,6-trien-3-one, the deconjugation and reduction afforded 3P-hydroxycholesta-l,5,7-triene (95) (59). The 5,7-diene system was then protected as its 4-phenyl-l,2,4-triazoline-3,5-dione (PTD) adduct (96). Treatment of (96) with m-chloroperbenzoic acid gave a 5 3 mixture of the lp,2p- and la,2a-epoxides (98). More recently, Whalley and his co-workers have found that if the dimethyl-t-... 

Formation of the secondary alcohol 71 clearly indicates that reaction of the alkene and the Lewis acid gives the more stable secondary carbocation. Indeed, this is the mechanism for this transformation, as discussed in further detail later. The overall transformation is a hydration process that adds water to the more substituted carbon of the alkene (sometimes called a Markovnikov addition), followed by removal of mercury, and is called oxymercuration-demercuration or simply oxymercuration. 

Alcohols can be prepared from a variety of other functional groups, including by reduction of a carbonyl, hydration of an alkene, or substitution of a leaving group. Remember, regiochemistry is a concern when starting with an alkene, and water can be added with either Markovnikov (oxymercuration-demercuration) or anti-Markovnikov (hydroboration-oxidation) orientation. 

In the laboratory, alkenes are often hydrated by the oxymercuration-demercuration procedure. Oxymercuration involves electrophilic addition of Hg2+ to the alkene on reaction with mercury(II) acetate [(CH3C02)2Hg, often abbreviated Hg(OAc)2] in aqueous tetrahydrofuran (THF) solvent. When the intermediate organomercury compound is then treated with sodium borohydride, NaBH4, demercuration occurs to produce an alcohol. For example ... 

The alcohol obtained after demercuration is the same as the product of Markovnikov hydration (Section 12-4) of the starting material. However, oxymercuration-demercuration is a valuable alternative to acid-catalyzed hydration, because no carbocation is involved therefore oxymercuration-demercuration is not susceptible to the rearrangements that commonly occur under acidic conditions (Section 12-3). Its use is limited by the expense of the mercury reagent and its toxicity, which requires careful removal of mercury from the product and safe disposal. 

Oxymercuration/demercuration has thus been suggested as a mild procedure for the Markovnikov hydration of carbon-carbon double bonds. As shown in Chapter 3, hydroboration followed by oxidation can be used for their hydration contrary to Markovnikov s rule. The two reaction sequences are compared below for 1-hexene ... 

Write the structure of the product of oxymercuration-demercuration of 3,3-dimethyU-butene. Is this product the same as would be obtained by the acid-catalyzed hydration of the alkene ... 

The first stage, oxymercuration, involves addition to the carbon-carbon double bond of —OH and —HgOAc. Then, in demercuration, the —HgOAc is replaced by —H. The reaction sequence amounts to hydration of the alkene, but is much more widely applicable than direct hydration. 

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