Anti-Markovnikov addition of HBr to alkenes

A Summary of Markovnikov versus Anti-Markovnikov Addition of HBr to Alkenes... 

The anti-Markovnikov addition of HBr to alkenes was probably the first free-radical addition reaction to be discovered. The discovery was inadvertent around the turn of the twentieth century, scientists studying the regiochemistry of addition of HBr to alkenes found that the proportion of Markovnikov to anti-Markovnikov addition products varied inexplicably from run to run. Eventually, it was discovered that impurities such as O2 and peroxides greatly increased the amount of anti-Markovnikov addition product. The results were later explained by a free-radical addition mechanism. The anti-Markovnikov regiochemistry derives from the addi-ton of the Br- radical to the less substituted C of the alkene (steric reasons) to give the lower energy, more substituted radical (electronic reasons). In a polar reaction, Br- would add to the more substituted C of the alkene. 

The reaction with HBr is also significant in terms of regiochemistry. The reaction results in the anti-Markovnikov orientation, with the bromine adding to the less-substituted carbon of the double bond. The anti-Markovnikov addition of HBr to alkenes was one of the earliest free radical reactions to be put on a firm mechanistic basis. In the presence of a suitable initiator, such as a peroxide, a radical chain mechanism becomes competitive with the ionic mechanism for addition of HBr. 

Credit has also been given to Hey and Waters for independent discovery of the radical nature of anti-Markovnikov addition of HBr to alkenes Hey, D. H. Waters, W. A. Chem. Rev. 1937, 21,169. 

This radical anti-Markovnikov addition of HX to alkenes is restricted to HBr both HI and HCl add in a Markovnikov fashion by an ionic... 

This process has been coupled with meta addition of a carbonyl anion equivalent and the controlled exo addition of the incoming nucleophile to generate acorenone and acorenone B stereospecifically from [(o-methylanisole)Cr(CO)3] (63 Scheme 14).123 The first step is addition of a cyanohydrin acetal anion (64) to the less-hindered meta position in [(o-methylanisole)Cr(CO)3]. Addition of allylMgBr to the resulting ketone, anti-Markovnikov addition of HBr to the alkene, substitution for Br by CN, and coordina-... 

Another common propagation step is addition of a radical to a double or triple bond as in the anti-Markovnikov addition of HBr to an alkene (Scheme 4.31). Carbon tetrachloride can be added to propylene in 80% yield (Scheme 4.32). 

The addition of hydrogen halides to simple alkenes, in the absence of peroxides, takes place by an electrophilic mechanism, and the orientation is in accord with Markovnikov s rule. " When peroxides are added, the addition of HBr occurs by a free-radical mechanism and the orientation is anti-Markovnikov (p. 985). It must be emphasized that this is true only for HBr. Free-radical addition of HF and HI has never been observed, even in the presence of peroxides, and of HCl only rarely. In the rare cases where free-radieal addition of HCl was noted, the orientation was still Markovnikov, presumably beeause the more stable product was formed. Free-radical addition of HF, HI, and HCl is energetically unfavorable (see the discussions on pp. 900, 910). It has often been found that anti-Markovnikov addition of HBr takes place even when peroxides have not been added. This happens because the substrate alkenes absorb oxygen from the air, forming small amounts of peroxides... 

Anti-Markovnikov free-radical-induced addition of HBr to alkenes can be prevented by carrying out the reaction in the presence of small amounts of antioxidants that inhibit the reaction of oxygen with the alkene to form peroxides. 

A well-known example of the application of mechanistic understanding to help to control product yields is also of commercial significance - the addition of HBr to alkenes which may occur via cationic or radical mechanisms, Scheme 2.1 [2a]. Very pure alk-l-enes (1), in the absence of peroxides, react to give the 2-bromo-products (2) by Markovnikov addition. In the presence of peroxides or other radical sources, anti-Markovnikov addition gives the 1-bromo-products (3). 

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. 

Neither product has its alcohol functional group on the carbon atom that is functionalized in the target compound. Alcohol C needs its functional group moved two carbon atoms, but alcohol D needs it moved only one carbon atom. Converting alcohol D to an alkene functionalizes the correct carbon atom Anti-Markovnikov addition of HBr converts the alkene to an alkyl halide with the bromine atom on the correct carbon atom. 

The other reaction is the peroxide-catalysed addition of HBr to alkenes 7.19 giving the anti-Markovnikov product 7.21. The peroxide generates a bromine radical by abstracting the hydrogen atom from the HBr. The key step is the addition of the bromine atom to the double bond 7.19, which takes place to give the more-substituted radical 7.20, and this in turn abstracts a hydrogen atom from another molecule of HBr to give the primary alkyl bromide 7.21. 

Scheme 11.5 gives some examples of these radical addition reactions. Entries 1 to 3 show anti-Markovnikov addition of HBr. The reaction in Entry 1 was carried out by passing HBr gas into the alkene, using benzoyl peroxide as the initiator, apparently near room temperature. Entry 2 is an example of anti-Markovnikov addition to... 

In the addition of HBr, the peroxide effect is the historical initiation procedure. In the 1930s, the addition of HBr to alkenes was found to be both Markovnikov and anti-Markovnikov by various laboratories, and some laboratories found both results under seemingly identical conditions. Kharasch and Mayo found that in the presence of peroxides and often air, the anti-Markovnikov addition prevailed, while "clean" conditions gave Markovnikov addition. It is now clear that the anti-Markovnikov results arose from the presence of peroxides, often in trace amounts in ether solvents, which initiated radical chain reactions. 

In Summary Radical initiators alter the mechanism of the addition of HBr to alkenes from ionic to radical chain. The consequence of this change is anti-Markovnikov regioselectivity. Other species, most notably thiols, but not HCl or HI, are capable of undergoing similar reactions. 

Early investigations of the addition of HBr to alkenes tended to give some of the anti-Markovnikov as well as the expected Markovnikov products. Amounts were variable and depended on the reaction conditions and, in some cases, the care of the experimenter. The cause of this was that atmospheric oxygen was reacting with the HBr to give bromine radicals—and these reacted with alkenes by a different mechanism, and with a different regiochemistry from that for HBr in polar... 

Now let s draw the forward scheme. The 3° alcohol is converted to 2-methylpropene using strong acid. Anti-Markovnikov addition of HBr (with peroxides) produces l-bromo-2-methylpropane. Subsequent reaction with sodium acetylide (produced from the 1° alcohol by dehydration, bromination and double elimation/deprotonation as shown) produces 4-methyl-1-pentyne. Deprotonation with sodium amide followed by reaction with 1-bromopentane (made from the 2° alcohol by tosylation, elimination and anfi -Markovnikov addition) yields 2-methyl-4-decyne. Reduction using sodium in liquid ammonia produces the E alkene. Ozonolysis followed by treatment with dimethylsulfide produces an equimolar ratio of the two products, 3-methylbutanal and hexanal. 

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. 

Two reaction types that are commonly confused with one another are 8.478.5—addition of HBr to an alkene (Markovikov or anti-Markovnikov), and 15.2—radical halogenation using NBS or Br2 and light. This is especially confusing when substituting for an allylic H on an alkene. 

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... 

It is possible to obtain anti-Markovnikov products when HBr is added to alkenes in the presence of free radical initiators, e.g. hydrogen peroxide (HOOH) or alkyl peroxide (ROOR). The free radical initiators change the mechanism of addition from an electrophilic addition to a free radical addition. This change of mechanism gives rise to the anh-Markovnikov regiochemistry. For example, 2-methyl propene reacts with HBr in the presence of peroxide (ROOR) to form 1-bromo-2-methyl propane, which is an anh-Markovnikov product. Radical additions do not proceed with HCl or HI. 

Addition of HBr in nonpolar solvents to terminal alkenes was found to give anti-Markovnikov products even under nonradical conditions.122 Products formed in both the normal and abnormal additions may be obtained in near-quantitative yields by changing the temperature and the reagent reactant ratio 122... 

In 1933, M. S. Kharasch and F. W. Mayo found that some additions of HBr (but not HC1 or HI) to alkenes gave products that were opposite to those expected from Markovnikov s rule. These anti-Markovnikov reactions were most likely when the reagents or solvents came from old supplies that had accumulated peroxides from exposure to the air. Peroxides give rise to free radicals that initiate the addition, causing it to occur by a radical mechanism. The oxygen-oxygen bond in peroxides is rather weak, so it can break to give two alkoxy radicals. 

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