Markovnikov addition orientation

Organoboranes react with a mixture of aqueous NH3 and NaOCl to produce primary amines. It is likely that the actual reagent is chloramine NH2CI. Chloramine itself,hydroxylamine-O-sulfonic acid in diglyme, and trimethyl-silyl azide " also give the reaction. Since the boranes can be prepared by the hydroboration of alkenes (15-16), this is an indirect method for the addition of NH3 to a double bond with anti-Markovnikov orientation. Secondary amines can be prepared by the treatment of alkyl- or aryldichloroboranes or dialkylchlorobor-anes with alkyl or aryl azides. 

Thus the observed orientation in both kinds of HBr addition (Markovnikov electrophilic and anti-Markovnikov free radical) is caused by formation of the secondary intermediate. In the electrophilic case, it forms because it is more stable than the primary in the free-radical case because it is sterically preferred. The stability order of the free-radical intermediates is also usually in the same direction 3°>2°>1° (p. 241), but this factor is apparently less important than the steric factor. Internal alkenes with no groups present to stabilize the radical usually give an approximately 1 1 mixture. 

Secondary amines can be added to certain nonactivated alkenes if palladium(II) complexes are used as catalysts The complexation lowers the electron density of the double bond, facilitating nucleophilic attack. Markovnikov orientation is observed and the addition is anti An intramolecular addition to an alkyne unit in the presence of a palladium compound, generated a tetrahydropyridine, and a related addition to an allene is known.Amines add to allenes in the presence of a catalytic amount of CuBr " or palladium compounds.Molybdenum complexes have also been used in the addition of aniline to alkenes. Reduction of nitro compounds in the presence of rhodium catalysts, in the presence of alkenes, CO and H2, leads to an amine unit adding to the alkene moiety. An intramolecular addition of an amine unit to an alkene to form a pyrrolidine was reported using a lanthanide reagent. 

Another convenient procedure for hydrochlorination involves adding trimethylsilyl chloride to a mixture of an alkene and water. Good yields of HC1 addition products (Markovnikov orientation) are formed.3 4 These conditions presumably involve generation of HC1 by hydrolysis of the silyl chloride, but it is uncertain if the silicon plays any further role in the reaction. 

Compared to a bromonium ion, the C-S bonds are stronger and the TS for nucleophilic addition is reached later. This is especially true for the sulfurane structures. Steric interactions that influence access by the nucleophile are a more important factor in determining the direction of addition. For reactions involving phenylsulfenyl chloride or methylsulfenyl chloride, the intermediate is a fairly stable species and ease of approach by the nucleophile is the major factor in determining the direction of ring opening. In these cases, the product has the anti-Markovnikov orientation.62... 

The overall transformation of alkenes to alcohols that is accomplished by epoxi-dation and reduction corresponds to alkene hydration. Assuming a nucleophilic ring opening by hydride addition at the less-substituted carbon, the reaction corresponds to the Markovnikov orientation. This reaction sequence is therefore an alternative to the hydration methods discussed in Chapter 4 for converting alkenes to alcohols. 

Both electronic and steric factors accounts for the anti-Markovnikov orientation of the addition. 

Electrophilic addition of HBr to propene gives predominantly the so-called Markovnikov orientation Markovnikov s rule states that addition of HX across a carbon-carbon multiple bond proceeds in such a way that the proton adds to the less-substituted carbon atom, i.e. that already bearing the greater number of hydrogen atoms (see Section 8.1.1). We rationalized this in terms of formation of the more favourable carbocation, which in the case of propene is the secondary carbocation rather than the alternative primary carbocation. 

Now, just the same sort of rationalization can be applied to the radical addition, in that the more favourable secondary radical is predominantly produced. This, in turn, leads to addition of HBr in what is the anti-Markovnikov orientation. The apparent difference is because the electrophile in the ionic mechanism is a proton, and bromide then quenches the resultant cation. In the radical reaction, the attacking species is a bromine atom, and a hydrogen atom is then used to quench the radical. This is effectively a reverse sequence for the addition process but, nevertheless, the stability of the intermediate carbocation or radical is the defining feature. The terminologies Markovnikov or anti-Markovnikov orientation may be confusing and difficult to remember consider the mechanism and it all makes sense. 

Kharasch and Mayo in 1933," in the first of many papers on the subject, showed that the addition of HBr to allyl bromide in the presence of light and air occurs rapidly to yield 1,3-dibromopropane, whereas in the absence of air and with purified reagents, the reaction is slow and 1,2-dibromopropane is formed. The latter reaction is the normal addition occurring by an ionic pathway giving the Markovnikov orientation. In 1933 the mechanism of the abnormal process ( anti-Markovnikov addition) was not discussed, and it was only in 1937 that the free radical chain mechanism for this process was proposed by Kharasch and his co-workers. "" The mechanism was extended to propene, for which the role of peroxides in promoting the reaction was demonstrated (equations 30, 31). This mechanism was also proposed... 

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. 

Thus the observed orientation in both kinds of HBr addition (Markovnikov electrophilic and anti-Markovnikov free radical) is caused by formation of the secondary intermediate. 

Water can be added indirectly, with anti-Markovnikov orientation, by treatment of the alkene with a 1 1 mixture of PhCH2NEt3+ BH4 and Me3SiCl, followed by addition of an aqueous solution of K2C03.152 For another method of anti-Markovnikov hydration, see 5-12. With substrates of the type C=C—Z (Z is as defined on p. 741) the product is almost always HO—C—CH—Z and the mechanism is usually nucleophilic,153 though electrophilic... 

Secondary amines can be added to certain nonactivated olefins if palladium(II) complexes are used as catalysts.208 The complexation lowers the electron density of the double bond, facilitating nucleophilic attack.209 Markovnikov orientation is observed and the addition is anti.210... 

Hypobromous (HOBr) and hypoiodous (IOH) acids can be generated from NaBrOs and H5IO6, respectively, by reduction with NaHSC>3 in MeCN/H20. Markovnikov orientation and awfi-stereochemistry has been observed on addition of these reagents to a variety of olefins186. 

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. 

The addition of water to alkynes is also aided by the presence of mercury (II) salts. The reaction is usually conducted in water, with the presence of a strong acid, such as sulfuric acid, and a mercury salt, such as HgS04 oi HgO. In this case the mercury is spontaneously replaced by hydrogen under the reaction conditions, so a second step is not necessary. The addition occurs with a Markovnikov orientation stereochemistry is not an issue. 

Well before the wide use of organoselenium compounds in chemistry, it was discovered that electrophilic selenium compounds of the type RSeX add stereospecifically to alkenes.45 Since that time this reaction has been an important tool in the portfolio of organic chemists and has been used even for the construction of complex molecules. Comprehensive reviews on this chemistry have appeared46-49 and in recent times the synthesis of chiral selenium electrophiles and their application in asymmetric synthesis has emerged. As shown in Scheme 1, the addition reactions of selenium electrophiles to alkenes are stereospecific anti additions. They involve the initial formation of seleniranium ion intermediates 1 which are immediately opened in the presence of nucleophiles. External nucleophiles lead to the formation of addition products 2. The addition to unsymmetrically substituted alkenes follows the thermodynamically favored Markovnikov orientation. The seleniranium ion intermediates of alkenes with internal nucleophiles such as 3 will be attacked intramolecularly to yield cyclic products 4 and 5 via either an endo or an exo pathway. Depending on the reaction conditions, the formation of the seleniranium ions can be reversible. 

This is the original statement of Markovnikov s rule. Reactions that follow this rule are said to follow Markovnikov orientation and give the Markovnikov product. We are often interested in adding electrophiles other than proton acids to the double bonds of alkenes. Markovnikov s rule can be extended to include a wide variety of other additions, based on the addition of the electrophile in such a way as to produce the most stable carbocation. 

Radical Addition of HBr to Unsymmetrical Alkenes Now we must explain the anti-Markovnikov orientation found in the products of the peroxide-catalyzed reaction. With an unsymmetrical alkene like 2-methylbut-2-ene, adding the bromine radical to the secondary end of the double bond forms a tertiary radical. 

This synthesis requires the addition of HBr to an alkene with Markovnikov orientation. Ionic addition of HBr gives the correct product. 

Oxymercuration-demercuration of an unsymmetrical alkene generally gives Markovnikov orientation of addition, as shown by the oxymercuration of propene in the preceding example. The mercurinium ion has a considerable amount of positive charge on both of its carbon atoms, but there is more of a positive charge on the more substituted carbon atom, where it is more stable. Attack by water occurs on this more electrophilic carbon, giving Markovnikov orientation. The electrophile, +Hg(OAc), remains... 

The solvent attacks the mercurinium ion at the more substituted end of the double bond (where there is more <5+ charge), giving Markovnikov orientation of addition. The Hg(OAc) group appears at the less substituted end of the double bond. Reduction gives the Markovnikov product, with hydrogen at the less substituted end of the double bond. 

The boron atom is removed by oxidation, using aqueous sodium hydroxide and hydrogen peroxide (HOOH or H2C>2) to replace the boron atom with a hydroxyl (—OH) group. The oxidation does not affect the orientation of the product, because the anti-Markovnikov orientation was established in the first step, the addition of BH3. 

A reaction in which one direction of bond making or bond breaking occurs preferentially over all other directions. For example, the addition of HC1 is regioselective, predicted by Markovnikov s rule. Hydroboration-oxidation is regioselective because it consistently gives anti-Markovnikov orientation, (p. 332)... 

In Section 8-3B, we saw the effect of peroxides on the addition of HBr to alkenes. Peroxides catalyze a free-radical chain reaction that adds HBr across the double bond of an alkene in the anti-Markovnikov sense. A similar reaction occurs with alkynes, with HBr adding with anti-Markovnikov orientation. 

Mercuric Ion-Catalyzed Hydration Alkynes undergo acid-catalyzed addition of water across the triple bond in the presence of mercuric ion as a catalyst. A mixture of mercuric sulfate in aqueous sulfuric acid is commonly used as the reagent. The hydration of alkynes is similar to the hydration of alkenes, and it also goes with Markovnikov orientation. The products are not the alcohols we might expect, however. 

Hydroboration-Oxidation In Section 8-7 we saw that hydroboration-oxidation adds water across the double bonds of alkenes with anti-Markovnikov orientation. A similar reaction takes place with alkynes, except that a hindered dialkylborane must be used to prevent addition of two molecules of borane across the triple bond. Di(second-ary isoamyl)borane, called disiamylborane, adds to the triple bond only once to give a vinylborane. (Amyl is an older common name for pentyl.) In a terminal alkyne, the boron atom bonds to the terminal carbon atom. 

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