Markovnikov additions regioselective reactions

Anti-Markovnikov addition (Sections 6.8, 6.11) Addition reaction for which the regioselectivity is opposite to that predicted on the basis of Markovnikov s rule. 

The stoichiometric hydroamination of unsymmetrically disubstituted alkynes is highly regioselective, generating the azametaUacycle with the larger alkyne substituent a to the metal center [294, 295]. In others words, the enamine or imine formed results from an anti-Markovnikov addition. Unfortunately, this reaction could not be applied to less stericaUy hindered amines. 

The most synthetically valuable method for converting alkynes to ketones is by mercuric ion-catalyzed hydration. Terminal alkynes give methyl ketones, in accordance with the Markovnikov rule. Internal alkynes give mixtures of ketones unless some structural feature promotes regioselectivity. Reactions with Hg(OAc)2 in other nucleophilic solvents such as acetic acid or methanol proceed to (3-acetoxy- or (3-methoxyalkenylmercury intermediates,152 which can be reduced or solvolyzed to ketones. The regiochemistry is indicative of a mercurinium ion intermediate that is opened by nucleophilic attack at the more positive carbon, that is, the additions follow the Markovnikov rule. Scheme 4.8 gives some examples of alkyne hydration reactions. 

The addition of hydrogen halide to alkene is another classical electrophilic addition of alkene. Although normally such reactions are carried out under anhydrous conditions, occasionally aqueous conditions have been used.25 However, some difference in regioselectivity (Markovnikov and anti-Markovnikov addition) was observed. The addition product formed in an organic solvent with dry HBr gives exclusively the 1-Br derivative whereas with aq. HBr, 2-Br derivative is formed. The difference in the products formed by the two methods is believed to be due primarily to the difference in the solvents and not to the presence of any peroxide in the olefin.26... 

When the same substituents are at each end of the double or triple bond, it is called symmetrical. Unsymmetrical means different substituents are at each end of the double or triple bond. Electrophilic addition of unsymmetrical reagents to unsymmetrical double or triple bonds follows Markovnikov s rule. According to Markovnikov s rule, addition of unsymmetrical reagents, e.g. HX, H2O or ROH, to an unsymmetrical alkene proceeds in a way that the hydrogen atom adds to the carbon that already has the most hydrogen atoms. The reaction is not stereoselective since it proceeds via a planar carbocation intermediate. However, when reaction proceeds via a cyclic carbocation intermediate, it produces regiospecific and stereospecific product (see below). A regioselective reaction is a reaction that can potentially yield two or more constitutional isomers, but actually produces only one isomer. A reaction in which one stereoisomer is formed predominantly is called a stereoselective reaction. 

Hydroboration-oxidation of alkenes preparation of alcohols Addition of water to alkenes by hydroboration-oxidation gives alcohols via anti-Markovnikov addition. This addition is opposite to the acid-catalysed addition of water. Hydrohoration is regioselective and syn stereospecific. In the addition reaction, borane bonds to the less substituted carbon, and hydrogen to the more substituted carbon of the double bond. For example, propene reacts with borane and THF complex, followed by oxidation with basic hydrogen peroxide (H2O2), to yield propanol. 

Hydroboration-oxidation of alkynes preparation of aldehydes and ketones Hydroboration-oxidation of terminal alkynes gives syn addition of water across the triple bond. The reaction is regioselective and follows anti-Markovnikov addition. Terminal alkynes are converted to aldehydes, and all other alkynes are converted to ketones. A sterically hindered dialkylborane must be used to prevent the addition of two borane molecules. A vinyl borane is produced with anU-Markovnikov orientation, which is oxidized by basic hydrogen peroxide to an enol. This enol tautomerizes readily to the more stable keto form. 

The stoichiometric equivalents of halogen fluorides, i.e. chlorine monofluoride, bromine monofluoride and iodine monofluoride, have found a wide application in addition reactions to double bonds. The equivalents are obtained by reacting A -haloamides or free halogens in combination with hydrogen fluoride or its salts as the source of fluoride ions. The reactions proceed under mild conditions at — 80 to 20 "C in anhydrous hydrofluoric acid or diethyl ether, tetrahydro-furan, dichloromethane or chloroform mainly by electrophilic addition with Markovnikov-type regioselectivity (anti addition).26-28... 

These reactions illustrate the importance of ruthenium vinylidene species, as activated forms of terminal alkynes, in catalysis, because they favor the addition of O-nudeophiles (carbamic and carboxylic acids, alcohols, water) to terminal alkynes and completely reverse the expected regioselectivity of the addition. These examples also show that the activation processes are very sensitive to the nature of the nucleophiles, and the success of the awtt-Markovnikov addition to terminal alkynes is highly dependent on both the electron richness and steric hindrance of the ancillary ligands coordinated to the active site. 

From the Hg-containing alcohol in Figure 3.38 and NaBH4 one can obtain the Hg-free alcohol. The overall result is a hydration of the C=C double bond. According to the nomenclature of Section 3.3.3, its regioselectivity corresponds to a Markovnikov addition. It is complementary to the regioselectivity of the reaction sequence hydro-boration/oxidation/hydrolysis (Table 3.1). The latter sequence would have converted the same olefin regioselectively into the primary instead of the secondary alcohol. 

In contrast to olefins, little is known on catalytic hydroboration of conjugated dienes. Suzuki and Miyaura20 described a 1,4-addition of catecholborane to acyclic 1,3-dienes, catalyzed with tetrakis(triphenylphosphine)pa]ladium(0). An interesting Markovnikov type regioselectivity was observed in the enantioselective dihydroboration of (E)-1-phenyl-1,3-butadiene with catecholborane, catalyzed by chiral rhodium complexes.21 However, the scope of these reactions is not well known, and the choice of catalysts is very limited. 

So far we have looked at the addition of electrophiles to carbon/carbon double bonds that have followed the Markovnikov regioselectivity. Now we will study reactions that adopt the opposite regioselectivity, i.e. an a Z/-Markovnikov addition. From a synthetic point of view, obviously, it is useful to have the choice. 

Cation radicals of arylcyclopropanes, produced by photoinduced one-electron transfer to an electron acceptor, undergo ring-opening reactions accompanied by regioselective polar additions. 1,4-Dicyanobenzene (5) sensitized photolysis of l,l-bis(4-tolyl)cyclopropane (4) in methanol/acetonitrile resulted exclusively in anti-Markovnikov addition of methanol to the cyclopropane. It is assumed that excitation of 5 followed by electron transfer from 4 gives a dicyanobenzene radical anion 5(- ) - cyclopropane radical cation 4(4-) pair. Attack by methanol on the radical cation 4(4-) followed by proton loss affords benzylic radical 7 that is reduced by 5( —) to give benzylic anion 8 and quenched by methanol to afford product... 

In summary, the stereochemistry of the halogenation of alkenes is not easily predicted. Addition of fluorine is mostly syn, while anti addition prevails with all other halogens and interhalogens. In most cases interhalogens show Markovnikov-type regioselectivity in their reactions with unsymmetrical olefins but enantioselective methods for the addition of halogens are still rare. 

The regioselectivity of addition of hydrogen bromide to alkenes can be complicated if a free-radical chain addition occurs in competition with the ionic addition. The free-radical chain reaction is readily initiated by peroxidic impurities or by light and leads to the anti Markovnikov addition product. The mechanism of this reaction is considered more fully in Chapter 11. Conditions that minimize the competing radical addition include use of high-purity alkene and solvent, exclusion of light, and addition of a radical inhibitor. ... 

Markovnikov addition, - of simple alkenes. In other words, addition of HCl, HBr, or HI to substituted alkenes will lead to an alkyl halide where the nucleophile is attached to the more substituted carbon of the Jt-bond. The basis of this regioselectivity is, of course, formation of the more stable carbocation, 295, which is attacked by bromide ion to give 1-bromo-l-methylcyclohexane (296). This is the normal course of all reactions with acid and an alkene if the intermediate is a cation. In section 2.7.B.ii, the reaction of 100 with HCl is an example of this type of reaction. 

Mannich reaction Alkylation of enols by electrophilic iminium ions, giving f)-aminocarbonyl compounds. Markovnikov rule Regioselectivity in electrophilic addition to alkenes whereby an electrophile attacks... 

The Wacker reaction has been applied to numerous simple olefins such as a-olefins and cycloalkenes, or to functionalized olefins such nitroethylene, acrylonitrile, styrene, allyl alcohol, or maleic acid [3]. The carbonyl group is formed at the carbon atom of the double bond where the nucleophile would add in a Markovnikov addition. Reversal of the regioselectivity has only been observed with particular substrates such as 1,5-dienes [9]. Conversion and selectivity for the oxidation of these olefins were found to be very dependent on the water solubility of the olefin. Indeed, high molecular weight olefins do not react under the standard... 

Chemists describe reactions like the Markovnikov additions of hydrogen halides to alkenes as being regioselective. Regio comes from the Latin word regionem meaning direction. 

Hydroboration—oxidation reactions are regioselective the net result of hydroboration—oxidation is anti-Markovnikov addition of water to an alkene. 

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