Oxymercuration Reactions

Oxymercuration Reactions.— Two research groups have drawn attention to the value of the oxymercuration-demercuration reaction when applied to unsaturated long-chain compounds  

The simple reaction with mercuric acetate and methanol, followed by reduction with sodium borohydride, converts methyl oleate, for example, into a mixture of methyl 9- and 10-methoxystearates. Other mono- and poly-enoic esters behave in a similar way and it is possible by g.c.—m.s. to identify these reaction products and so determine the position of unsaturation in the original ester.  

The methanol can be replaced by other nucleophilic solvents such as ethanol, acetic acid, or water (in tetrahydrofuran as cosolvent) to give the corresponding ethoxy-, acetoxy-, or hydroxy-esters. Cyclic ethers (substituted tetrahydrofurans and tetrahydropyrans) are formed by intramolecular reaction when the unsaturated ester also contains an appropriately placed hydroxy-group, even in the presence of a reactive solvent. This has been developed into a procedure for the identification, analysis, and isolation of long-chain alcohols and acids having alkene unsaturation in positions 3 (trans only), 4 (cis or tram), or 5 (cis or trans) Such acids (or natural mixtures in which they are present) are reduced to alcohols and subjected to oxymercuration (in DMF as a non-participating solvent) and demercuration. Cyclic ethers are formed only when there is unsaturation at positions 3,4, or 5 other double bonds are unaffected. For example, methyl arachidonatc 

Cyclic ethers are readily separated from unreacted alcohols and from one another by t.l.c. and g.l.c. If necessary, unreacted alcohol can be separated from the mercury derivative, from which the unsaturated alcohol is easily regenerated. 

Hydrogenations with homogeneous and heterogeneous catalysts have been reviewed.  

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Surely one would hope not. What if one just used the mercuric nitrate monohydrate that is at hand. One s only real concern would be if the monohydrate water would interfere with the acetonitrile in a competing oxymercuration reaction. But could it really considering the massive excess of acetonitrile present All Strike can say is that someone, somewhere is gonna try it. And Strike would really, really like to hear about it. 

The electrophile in oxymercuration reactions, HgX or Hg " , is a soft acid and strongly polarizing. It polarizes the n electrons of an alkene to the extent that a three-center, two-... 

Monoalkylthallium(III) compounds can be prepared easily and rapidly by treatment of olefins with thallium(III) salts, i.e., oxythallation (66). In marked contrast to the analogous oxymercuration reaction (66), however, where treatment of olefins with mercury(II) salts results in formation of stable organomercurials, the monoalkylthallium(III) derivatives obtained from oxythallation are in the vast majority of cases spontaneously unstable, and cannot be isolated under the reaction conditions employed. Oxythallation adducts have been isolated on a number of occasions (61, 71,104,128), but the predominant reaction pathway which has been observed in oxythallation reactions is initial formation of an alkylthallium(III) derivative and subsequent rapid decomposition of this intermediate to give products derived by oxidation of the organic substrate and simultaneous reduction of the thallium from thallium(III) to thallium(I). The ease and rapidity with which these reactions occur have stimulated interest not only in the preparation and properties of monoalkylthallium(III) derivatives, but in the mechanism and stereochemistry of oxythallation, and in the development of specific synthetic organic transformations based on oxidation of unsaturated systems by thallium(III) salts. 

Scheme 4.1 includes examples of oxymercuration reactions. Entries 1 and 2 illustrate the Markovnikov orientation under typical reaction conditions. The high exo selectivity in Entry 3 is consistent with steric approach control on a weakly bridged (or open) mercurinium ion. There is no rearrangement, indicating that the intermediate is a localized cation. 

Fig. 22 (a) Oxymercuration reaction for Hg2+ sensing with 58. (b) Oxidation state-selective Pd/Pt catalytic production of fluorophores 61 and 62 from 60. Nonfluorescent 58 is selectively converted into strongly green fluorescent 59 and nonfluorescent 60 is either converted into strongly green fluorescent 61 or strongly greenish-yellow fluorescent 62... 

There are several useful means for preparation of organomercury compounds. The general metal-metal exchange reaction between mercury(II) salts and organolithium or magnesium compounds is applicable. The oxymercuration reaction discussed in Section... 

The oxymercuration reaction of various 2-substituted 1,4-benzodioxin derivatives 35 in the presence of a suspension of mercuric acetate in water/THF followed by treatment in situ with sodium chloride and then with sodium borohydride as a reducing agent provided in excellent yields the expected hemiketals 36 (Scheme 2) <1997X2061 >. 

It is clear that the mechanism in Scheme 25 parallels (at least from the qualitative point of view) the mechanism of the addition of bromine to olefins shown in Scheme 11. Kinetic investigations indicate that the oxymercuration reaction involves a series of fast equilibria until the mercuronium ion (53) is formed. The subsequent nucleophilic attack of the solvent is probably the rate-limiting step, as indicated by steric requirements in bulky alkenes111. In the bromine addition, the formation of the bromonium ion is the rate-limiting step (or the rate-limiting equilibrium). However, the olefin reactivities in both reactions (bromination and oxymercuration) are identical when steric effects in the TS of the two addition reactions are taken into account110. 

This is true for the addition of hydrogen halide (H-X), halogens (X-X) and other electrophilic reagents (NO —Cl, I — Nj, etc.) to cyclohexenes. The oxymercuration reaction (Hg(OAc>2) in the presence of several nucleophiles (H20, AcOH, ROH) is another well known example. 

Both, hydration and hydroalkoxylation of olefins are usually carried out under acid catalysis or by oxymercuration reactions, although reactions mediated by palladium or by other metals have recently begun to emerge. In the latter case, nucleophilic addition of the O—H group is favored by a cationic palladium species that activates... 

It is possible to regiospecifically add the hydroxy group to carbon 2 of 1-hexene by using either the oxymercuration reaction or acid-catalyzed hydration. However, it is not possible to selectively add a hydroxy group only to carbon 2 of 2-hexene because both carbons are monosubstituted. Therefore, the path starting from 1-hexene should be used. 

The oxymercuration reaction can be run in methanol as the solvent rather than water. Predict the product of this reaction ... 

The carbon-metal systems considered appropriate for this section (and not covered elsewhere in this series) are carbon-tin, carbon-mercury and, to a restricted extent, carbon-palladium bonds. Although or-ganomercurials and organostannanes have been studied for over a century, the former continue to attract attention because of their controlled formation by the Markovnikov oxymercuration reaction (OM) and its variants, and the latter because of newer and regiospecific methods for forming C—Sn bonds and oxidatively cleaving them. In both cases, signiticant examples of synthetically useful oxidations have... 

Oxymercaration (2, 265-267 3. 194). Brown and Geoghegan have investigated the relative reactivities of a number of olefins in the oxymercuration reaction in a 20 80 (v/v) mixture of water and THF. The following reactivity is observed terminal disubstituted > terminal monosubstituted > internal disubstituted > internal trisub-stituted > internal leirasubstitu ted. Thus steric factors play a major role in the reactivity of olefins. Increased substitution on the double bond and increased steric hindrance at the site of hydroxyl or mercury substituent attachment decrease the rate of reaction. In the case of olefins of the type RCH CHR, cts-oleiins are more reactive than the corre.sponding rra/i.s-olefins. Inclusion of the double bond in ring systems causes a moderate rate increase which varies somewhat with structure cyclohcxenc > cyclo-pentenc cyclooctene norbornene bicyclo[2.2.2]-octene-2. 

The mechanism of the mercurydD-catalyzed alkyne hydration reactioi is analogous to the oxymercuration reaction of alkenes (Section 7.4). Elec trophilic addition of mercury(II) ion to the alkyne gives a vinylic cation which reacts with water and loses a proton to yield a mercury-containii enol intermediate. In contrast to alkene oxymercuration, no treatment widi NaBH4 is necessary to remove the mercury the acidic reaction conditions alone are sufficient to effect replacement of mercury by hydrogen (Figure 8.3). 

The intramolecular version of the oxymercuration reaction affords cyclic ethers. Furthermore, treatment of organomercury compounds (R-HgX) with NaBH4 in DMF in the presence of O2 replaces the carbon-mercury bond by a carbon-oxygen bond and yields the corresponding alcohol (R-OH). ... 

Oxymercuration reactions are usually carried out in a three-component system involving an alkene, alkyne, or cyclopropane, a mercury compound HgX2, and a nucleophile HY, where HY may be HOH, ROH, HOOH, HOOR, or HOCOR and is frequently the solvent . Reactivity follows the sequence of Lewis acid strength in HgX2, with Hg(OCOMe)2 < Hg(OCOCF3)2, Hg(C104)2, and a steric sequence in alkene, with CH2=CH2 > RCH=CH2 > cis-RCH=CHR > trans-RCH=CHR > R2C=CHR > R2C=CR2. 

A good example of a metal ion as an electrophile is the oxymercuration reaction. The nucleophile is often solvent, usually water or an alcohol. The charge is distributed, so little rearrangement occurs. The mercury is removed in a subsequent reduction step. 

The addition of water to alkenes, to produce alcohols, requires the presence of either (i) a strong acid or (ii) mercury(II) acetate (in an oxymercuration reaction). In both cases, the reactions involve the Markovnikov addition of water (i.e. the OH becomes attached to the more substituted carbon). 

In analogy with other electrophilic additions, the mechanism of the oxymercuration reaction can be discussed in terms of a cationic intermediate. The cationic intermediate can be bridged mercurinium ion) or open, depending on the structure of the particular alkene. The intermediates can be detected by NMR in nonnucleophilic solvents. ° The addition is completed by attack of a nucleophile at the more positive carbon. 

Where do mercuration reactions fit into this picture A mercurinium ion has both similarities and differences, as compared with the intermediates that have been described for other electrophilic additions. The electrophile in oxymercuration reactions, +HgX or Hg +, is a soft Lewis acid and polarizes the TT-electrons of an alkene to the extent that a three-center two-electron bond is formed between mercury and the two carbons of the double bond. However, there is also back bonding from Hg +(i orbitals to the alkene tt orbital. There is weaker bridging in the mercurinium ion than in the three-center four-electron bonding of the bromonium ion. 

The cyclization reactions of manool derivatives have continued to attract attention. A synthesis of the strobane skeleton based on oxymercuration reactions of 13-epimanool has been described. The oxidation of sclareol by chromium salts has been re-examined in a series of papers. The circular dichroism curves of manoyl oxide and its 13-epimers have been examined. Some further 11-oxomanoyl oxide derivatives, coleonol E and F, (13) and (14),... 

The most common oxymercuration reaction involves alkene, an alcohol such as methanol, and a mercury salt such as the acetate. The intermediate (alkoxy mercuri-acetate) is easily reduced by alkaline NaBH4 to the alkoxy derivative (Scheme 11). When applied to methyl oleate, this reaction gives a mixture of methyl 9- and 10-methoxystearates in high yield. 

The problem of the oxymercuration reaction, and the deoxymercuration process, alluded to above, has only begun to resolve itself in the last few years. The problem has been fundamentally one of assigning stereochemistry and mechanistic pattern to the processes... 

Typically, the oxymercuration reaction is second order overall, first order in alkene and first order in mercuric salt. Vardhan and Bach concluded that the oxymercuration reaction involves fast equilihriiun formation of an intermediate (with fCi = ki/k i), followed by rate-limiting attack of the nucleophile on this species (with rate constant 2)- Thus, the rate law for the reaction would be... 

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